Abstract:
:In recent years physiologically based pharmacokinetic (PBPK) modeling has found frequent application in risk assessments where PBPK models serve as important adjuncts to studies on modes of action of xenobiotics. In this regard, studies on mode of action provide insight into both the sites/mechanisms of action and the form of the xenobiotic associated with toxic responses. Validated PBPK models permit calculation of tissue doses of xenobiotics and metabolites for a variety of conditions, i.e. at low-doses, in different animal species, and in different members of a human population. In this manner, these PBPK models support the low-dose and interspecies extrapolations that are important components of current risk assessment methodologies. PBPK models are sometimes referred to as physiological toxicokinetic (PT) models to emphasize their application with compounds causing toxic responses. Pharmacokinetic (PK) modeling in general has a rich history. Data-based PK compartmental models were developed in the 1930's when only primitive tools were available for solving sets of differential equations. These models were expanded in the 1960's and 1970's to accommodate new observations on dose-dependent elimination and flow-limited metabolism. The application of clearance concepts brought many new insights about the disposition of drugs in the body. In the 1970's PBPK/PT models were developed to evaluate metabolism of volatile compounds of occupational importance, and, for the first time, dose-dependent processes in toxicology were included in PBPK models in order to assess the conditions under which saturation of metabolic and elimination processes lead to non-linear dose response relationships. In the 1980's insights from chemical engineers and occupational toxicology were combined to develop PBPK/PT models to support risk assessment with methylene chloride and other solvents. The 1990's witnessed explosive growth in risk assessment applications of PBPK/PT models and in applying sensitivity and variability methods to evaluate model performance. Some of the compounds examined in detail include butadiene, styrene, glycol ethers, dioxins and organic esters/aids. This paper outlines the history of PBPK/PT modeling, emphasizes more recent applications of PBPK/TK models in health risk assessment, and discusses the risk assessment perspective provided by modern uses of these modeling approaches.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Andersen MEdoi
10.1016/s0378-4274(02)00375-2keywords:
subject
Has Abstractpub_date
2003-02-18 00:00:00pages
9-27issue
1-2eissn
0378-4274issn
1879-3169pii
S0378427402003752journal_volume
138pub_type
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journal_title:Toxicology letters
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journal_title:Toxicology letters
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doi:10.1016/0378-4274(84)90145-0
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2015.11.023
更新日期:2016-01-22 00:00:00
abstract::The potential adverse effects of hazardous waste incinerators (HWI) continue to be a subject of worry. The construction of the first and up till now only HWI in Spain finished in 1999. Twenty-six subjects employed at this HWI were divided into three groups: plant, laboratory and administration. Plasma analyses of HCB,...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2003.09.003
更新日期:2003-12-15 00:00:00
abstract::Human epidermal keratinocytes which have been cultured were treated with the heavy metal ions of cadmium, mercury, copper and zinc. Cytotoxicity was measured either by protein estimation or by using the neutral red assay. Antioxidants were added in order to find out whether heavy metal-induced cytotoxicity is related ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(94)90170-8
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2009.04.015
更新日期:2009-08-10 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章,评审
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更新日期:1996-08-01 00:00:00
abstract::The toxicity of benz (e) acephenanthrylene (BeA) has been studied earlier with regard to the carcinogenicity of its metabolites, but its phototogenotoxicity is not well understood. Present study aimed to analyze the photodynamic response of BeA in human skin cell line (A375) under ambient environmental intensity of UV...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2010.08.023
更新日期:2010-11-30 00:00:00
abstract::Quality control studies on cotinine measurements following low level environmental tobacco smoke (ETS) exposure are rare. The exposure to ETS was controlled and systematically changed in a series of experiments in a climatic chamber. Healthy nonsmoking volunteers were exposed to ETS simultaneously. The duration and le...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(87)90083-x
更新日期:1987-01-01 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2018.07.017
更新日期:2018-10-01 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(87)90140-8
更新日期:1987-08-01 00:00:00
abstract::1,3-Propane sultone is directly alkylating, genotoxic and carcinogenic. In rats, it induces local and systemic tumours at multiple target sites. Preponderant systemic tumours occur at the central nervous system, especially gliomas. Other localisations include the mammary gland, the intestine, the haematopoietic system...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/j.toxlet.2003.12.073
更新日期:2004-06-15 00:00:00
abstract::Untargeted metabolomic approaches offer new opportunities for a deeper understanding of the molecular events related to toxic exposure. This study proposes a metabolomic investigation of biochemical alterations occurring in urine as a result of dioxin toxicity. Urine samples were collected from Czech chemical workers ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2013.10.031
更新日期:2014-10-15 00:00:00
abstract::The intestinal epithelium is the first barrier against food contaminants and is highly sensitive to Fusarium toxins, especially deoxynivalenol (DON) and zearalenone (ZEA). Here, we explored the effects of low doses of DON and/or ZEA in naturally moldy diets on intestinal functions in piglets, including inflammatory re...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2020.07.032
更新日期:2020-10-15 00:00:00
abstract::In 2001 the SCOOP (SCOOP: Scientific Co-operation on Questions relating to Food) task 3.2.10 "Collection of occurrence data of Fusarium toxins in food and assessment of dietary intake by the population of EU Member States" was established. The task was divided in three subtasks (zearalenone, fumonisins and trichothece...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/j.toxlet.2004.04.045
更新日期:2004-10-10 00:00:00
abstract::Pregnant sows were fed a control diet (CON, 0.15 mg deoxynivalenol (DON) and 0.0035 mg zearalenone (ZON) per kg diet) or diet containing 15% of Fusarium toxin contaminated triticale (MYCO, 4.42 mg DON and 0.048 mg ZON per kg diet) during days 35-70 of gestation. All sows were fed in a restricted feeding regimen with t...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2008.04.016
更新日期:2008-07-10 00:00:00
abstract::For the past 10 years we have focused on the development of antisense treatments against viral infections such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV). We have demonstrated that phosphorothioate oligomers have in vitro anti-HIV activities and in vivo anti-HBV activity. In vitro anti-HIV activ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(95)03574-5
更新日期:1995-12-01 00:00:00
abstract::Vincristine (VCR) is commonly used to treat a variety of hematological malignancies and solid tumors in pediatric and adult patients. However, peripheral neuropathy is a dose-limiting side effect that leaves some patients with functional disability and long-term pain. Oxytocin (OT) has demonstrated analgesic and anti-...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2021.01.008
更新日期:2021-01-08 00:00:00
abstract::Elevated urinary trehalase activity was observed in the inhabitants of the Jinzu River basin. Urinary trehalase activity was correlated with other urinalysis components, such as beta 2-microglobulin, glucose, amino nitrogen, and cadmium, of which a high level was observed in cadmium-polluted areas as compared with the...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(86)90206-7
更新日期:1986-12-01 00:00:00
abstract::Excess alcohol consumption during pregnancy could lead to fetal alcohol syndrome (FAS). However, the molecular mechanism leading to craniofacial abnormality, a feature of FAS, is still poorly understood. The cranial neural crest cells (NCCs) contribute to the formation of the craniofacial bones. Therefore, NCCs expose...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2017.09.010
更新日期:2017-11-05 00:00:00
abstract::To understand the underlying mechanism for apoptosis induced by titanium dioxide nanoparticles (TNP), human airway epithelial cell line was cultured to investigate the relevant apoptosis pathways. Our results showed that the levels of reactive oxygen species and morphological apoptosis increased in a dose-dependent ma...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2010.03.014
更新日期:2010-06-16 00:00:00
abstract::A considerable body of research over the past fifteen years establishes that in laboratory animals the Ah (aromatic hydrocarbon) receptor (AhR) mediates most, if not all, toxic effects of halogenated aromatic hydrocarbons such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polyhalogenated bip...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/0378-4274(94)90139-2
更新日期:1994-01-01 00:00:00
abstract::This study describes two phases of a multi-phase project aiming to validate a mouse model for cow's milk allergy to assess the potential allergenicity of hydrolysed cow's milk based infant formulas (claim support EC-directive 2006/141/E). The transferability and the discriminatory power of this model was evaluated in ...
journal_title:Toxicology letters
pub_type: 杂志文章,多中心研究
doi:10.1016/j.toxlet.2013.04.008
更新日期:2013-06-20 00:00:00
abstract::The skin is an immunologically active tissue. Epidermal cells, both keratinocytes and Langerhans cells (LC), produce constitutively or can be stimulated to produce a variety of cytokines, many of which play important roles in the induction and regulation of allergic responses to sensitizing chemicals. Tumor necrosis f...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/0378-4274(95)03497-8
更新日期:1995-12-01 00:00:00
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journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(85)90018-9
更新日期:1985-11-01 00:00:00
abstract::Dimethocaine (DMC), a synthetic derivative of cocaine, is distributed and consumed as "new psychoactive substance" (NPS) without any safety testing at the forefront. It is mainly metabolized by N-acetylation, N-deethylation or hydroxylation. Therefore, the aim of the presented study was to determine the human NAT and ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2013.11.033
更新日期:2014-02-10 00:00:00
abstract::A computer program (Q-test) was used to evaluate the combined toxic effects of nerve agent GF and its combined form with sarin (GB/GF) in mice. Efficacy of Jielin Injection, the 2-PAM-containing antidote used successfully in China for the treatment of organophosphate pesticide poisoning, was also evaluated and compare...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/s0378-4274(97)00057-x
更新日期:1997-08-22 00:00:00
abstract::The repeated dose toxicity of tetrabromobisphenol A (TBBPA), a flame retardant, was examined in male and female newborn rats given TBBPA orally at 0, 40, 200, or 600 mg/kg per day for 18 days from 4 days of age until weaning at 21 days of age. Half the rats in each dose group were sacrificed for a full gross necropsy ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2004.01.001
更新日期:2004-04-21 00:00:00
abstract::Caloric restriction is known to reduce chemically-induced tumor incidence in laboratory animals. The effect is believed to be mediated in part by modification of hepatic drug metabolism, including both phase I and phase II enzymes. Using aflatoxin B1 (AFB1) as a model carcinogen, we studied the effect of caloric restr...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(92)90150-i
更新日期:1992-07-01 00:00:00
abstract::A single intraperitoneal injection of cadmium chloride (CdCl2, 0.32 mg/kg body weight) was administered to 15 adult female palm squirrels (Funambulus pennanti (Wroughton] and the hypothalamic 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) levels were quantified on the 1st, 7th and 40th day. 5-HT leve...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(88)90082-3
更新日期:1988-05-01 00:00:00