Application of benchmark dose risk assessment methodology to developmental toxicity: an industrial view.


:The U.S. EPA first signalled its intention to use benchmark dose risk techniques in 1991. Subsequently, publication of draft Guidelines for the Risk Assessment of Reproductive Toxicity data indicated the Agency's intention for wide use of the technique. In developmental toxicity experiments, a number of factors need to be considered before attempting benchmark dose calculations, as compared to the conventional NOAEL approach. For example, care in the assessment of potential litter effects (the litter is the unit of such a study) on the data and whether the data are continuous (e.g. foetal body weight) or discontinuous (e.g. specific or grouped developmental defects where the abnormality is present or absent). Two examples of the use of the benchmark dose approach will be made. First, in the analysis of foetal body weight, where a benchmark dose estimate for an agent producing a 5% decrease in mean foetal weight may be calculated from a shift in the distribution of foetal weights between groups, or by conversion of data to reflect changes in the incidence of 'small' pups (i.e. those towards the extreme of the normal range). The second example involves studies conducted on the developmental toxicity of a triazole antifungal. In the first study, the agent was clearly teratogenic, but a NOAEL was not established and thus necessitated a second study. Analysis of benchmark does estimates (e.g. for % foetuses malformed) from the first study indicated that these were not significantly changed when the data from the second study were combined (i.e. the second study did not aid the risk assessment). The benchmark dose approach has significant scientific and practical advantages over the conventional NOAEL methodology in risk assessments derived from developmental toxicity studies.


Toxicol Lett


Toxicology letters


Foster PM,Auton TR




Has Abstract


1995-12-01 00:00:00












  • In vitro metabolism of benzo[a]pyrene-7,8-dihydrodiol and dibenzo[def,p]chrysene-11,12 diol in rodent and human hepatic microsomes.

    abstract::Polycyclic aromatic hydrocarbons (PAHs) are contaminants that are ubiquitously found in the environment, produced through combustion of organic matter or petrochemicals, and many of which are procarcinogens. The prototypic PAH, benzo[a]pyrene (B[a]P) and the highly carcinogenic dibenzo[def,p]chrysene (DBC) are metabol...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Smith JN,Mehinagic D,Nag S,Crowell SR,Corley RA

    更新日期:2017-03-05 00:00:00

  • Polycyclic aromatic hydrocarbon coated onto Fe(2)O(3) particles: assessment of cellular membrane damage and antioxidant system disruption in human epithelial lung cells (L132) in culture.

    abstract::The aim of this study was to investigate the oxidative effects of Fe(2)O(3), benzo(a)pyrene (B(a)P) and pyrene, alone or in association (B(a)P or pyrene coated onto Fe(2)O(3) particles), in normal human embryonic lung epithelial cells (L132) in culture. We evaluated: (i) membrane integrity, through fatty acid release ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Garçon G,Shirali P,Garry S,Fontaine M,Zerimech F,Martin A,Hannothiaux MH

    更新日期:2000-09-30 00:00:00

  • Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde.

    abstract::Crotonaldehyde is an environment pollutant and lipid peroxidation product. Crotonaldehyde produces adverse effects to humans and serves as a risk factor for human pulmonary diseases. Like acrolein and 4-hydroxynonenal, crotonaldehyde seems likely to alter many cell signaling cascades, including inflammatory responses....

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Liu XY,Yang ZH,Pan XJ,Zhu MX,Xie JP

    更新日期:2010-08-16 00:00:00

  • Mercury concentrations in brain and kidney following ethylmercury, methylmercury and Thimerosal administration to neonatal mice.

    abstract::The distribution of mercury to the brain following an injection of methylmercury (MeHg) or ethylmercury (EtHg) was examined in immature mice. Postnatal day (PND) 16 CD1 mice received MeHg chloride either by IM injection or by gavage. At 24 h and 7 days post-injection, total mercury concentrations were determined in bl...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Harry GJ,Harris MW,Burka LT

    更新日期:2004-12-30 00:00:00

  • Metal environmental contamination within different human exposure context- specific and non-specific biomarkers.

    abstract::Exposure to high levels of persistent pollutants, such as metal mixtures, is commonly encountered by the general population especially in industrialized countries. The aim of this work was to evaluate how metal pollution in contaminated areas is reflected in terms of biomarkers (BMs) of exposure and effect in human su...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: de Andrade VL,Cota M,Serrazina D,Mateus ML,Aschner M,Dos Santos APM

    更新日期:2020-05-15 00:00:00

  • Cytogenetic effects induced by organophosphorus pesticides in mouse spermatocytes.

    abstract::Male mice (Q strain) received a single i.p. injection of 14 organophosphorus compounds, including 11 insecticides, administered on separate occasions. After a recovery period of 10 to 15 days, the cytogenic effects were analyzed in primary spermatocytes at diakinesis-metaphase I corresponding to the treatment of A4-B ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Degraeve N,Chollet MC,Moutschen J

    更新日期:1984-06-01 00:00:00

  • Toxicokinetic modeling and its applications in chemical risk assessment.

    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...

    journal_title:Toxicology letters

    pub_type: 杂志文章,评审


    authors: Andersen ME

    更新日期:2003-02-18 00:00:00

  • Genetic differences between C57BL/6 and DBA/2 mice in the inductions of UDP-glucuronyl transferases for 3-hydroxybenzo(a)pyrene, p-nitrophenol, and bilirubin by 3-methylcholanthrene.

    abstract::In C57BL/6 mice, aryl hydrocarbon hydroxylase (AHH) increased 1 day after treatment with 3-methylcholanthrene, and induction of UDP-glucuronyl transferases for 3-hydroxybenzo(a)pyrene, p-nitrophenol and bilirubin in the liver microsomes was observed 2 to 5 days later. In DBA/2 mice, neither AHH nor transferase activit...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Nemoto N,Takayama S

    更新日期:1980-01-01 00:00:00

  • Melamine, beyond the kidney: A ubiquitous endocrine disruptor and neurotoxicant?

    abstract::Melamine is commonly used in a variety of consumer products such as furniture, dining ware, and food utensils. The chemical infamously gained worldwide attention by its illegal addition to a variety of foodstuffs in order to falsify protein content, which led to serious, sometimes fatal, health impacts in children and...

    journal_title:Toxicology letters

    pub_type: 杂志文章,评审


    authors: Bolden AL,Rochester JR,Kwiatkowski CF

    更新日期:2017-10-05 00:00:00

  • Is the acceptable daily intake as presently used an axiom or a dogma?

    abstract::International scientific committees, regional scientific committees such as those of the European Union, and national regulatory agencies generally use the uncertainly factor approach for establishing acceptable or tolerable intakes of substances that exhibit thresholds of toxicity. No observed adverse effect levels (...

    journal_title:Toxicology letters

    pub_type: 杂志文章,评审


    authors: Galli CL,Marinovich M,Lotti M

    更新日期:2008-08-15 00:00:00

  • Cholestyramine as an antidote against paracetamol-induced hepato- and nephrotoxicity in the rat.

    abstract::Besides hepatotoxicity, paracetamol may exert nephrotoxic effects in experimental animals and man. The present study in rats shows that cholestyramine given 4 and 24 h after paracetamol provided protection against both hepato- and nephrotoxicity; this was evidenced by reduced increments in plasma enzyme activities (SD...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Siegers CP,Möller-Hartmann W

    更新日期:1989-05-01 00:00:00

  • Cadmium-binding proteins in human organs.

    abstract::Cadmium-binding proteins (CdBPs) in the cytosol fractions from several organs of man orally exposed to cadmium (Cd) were examined by gel chromatography. In kidney and liver most of the cadmium (76-87%) in the cytosols was bound to metallothionein, and hepatic metallothionein contained zinc also at a similar level. The...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Sato M,Takizawa Y

    更新日期:1982-05-01 00:00:00

  • A new physiological biomarker for nitrate exposure in humans.

    abstract::After toxicological studies with nitrate/nitrite in rats it was observed with nuclear magnetic resonance that N-methylnicotinamide (NMN), a metabolite of tryptophan was increased. The use of NMN as a biomarker for nitrate/nitrite exposure was investigated further in additional experiments with rats and in a human stud...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Jansen EH,van den Berg RH,Boink AB,Hegger C,Meulenbelt J

    更新日期:1995-05-01 00:00:00

  • Understanding the bioconjugation reaction of phenthoate with human serum albumin: New insights from experimental and computational approaches.

    abstract::Organophosphates are chemical pollutants that are existed widely in the environment, but the reactions of these agents with blood proteins are still not fully clarified. The current story was to analyze the static and dynamic interactions between human serum albumin (HSA) and phenthoate and then uncover the impact of ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Ding F,Peng W,Peng YK,Liu BQ

    更新日期:2019-10-10 00:00:00

  • Guanidinoacetic acid (GAA) synthesis in rat tubular suspension as a system for evaluating gentamicin (GM) nephrotoxicity.

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    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Takeda M,Jung KY,Sekine T,Endou H,Koide H

    更新日期:1995-11-15 00:00:00

  • Effects of cyanobacteria Oscillatoria sp. lipopolysaccharide on B cell activation and Toll-like receptor 4 signaling.

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    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Swanson-Mungerson M,Incrocci R,Subramaniam V,Williams P,Hall ML,Mayer AMS

    更新日期:2017-06-05 00:00:00

  • Role of neutrophils in acrylonitrile-induced gastric mucosal damage.

    abstract::Acrylonitrile (ACN) is a widely used intermediate in the manufacture of plastics, acrylic fibers, synthetic rubbers and resins that are used in a variety of products including food containers and medical devices. ACN is a possible human carcinogen and a documented animal carcinogen, with the stomach being an important ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Hamdy NM,Al-Abbasi FA,Alghamdi HA,Tolba MF,Esmat A,Abdel-Naim AB

    更新日期:2012-01-25 00:00:00

  • Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells.

    abstract::DNA-damaging agents are commonly used as anticancer therapeutics. Unfortunately, such drugs induced DNA damages as well as DNA repair are important in mediating drug resistance to cancer treatments. To evaluate changes in DNA repair proteins that occur in DNA damage agent treatment, we challenged human A549 lung adeno...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Shen YH,Chen BR,Cherng SH,Chueh PJ,Tan X,Lin YW,Lin JC,Chuang SM

    更新日期:2011-09-10 00:00:00

  • New developments in the therapy of intoxications.

    abstract::There has been a significant evolution in the clinical management of the poisoned patient over the last decade. Interventions that were once the cornerstone of treating the poisoned patient have become passé or have come under intense scrutiny. The advent of evidence-based medicine has forced clinical scientists to re...

    journal_title:Toxicology letters

    pub_type: 杂志文章,评审


    authors: Krenzelok EP

    更新日期:2002-02-28 00:00:00

  • Protection of Ewing's sarcoma family tumor (ESFT) cell line SK-N-MC from betulinic acid induced apoptosis by alpha-DL-tocopherol.

    abstract::Betulinic acid (BA) is known to induce apoptosis in melanoma neuroectodermal and malignant brain cancer cell lines. Present report describes the role of antioxidants on the BA-induced toxicity to human cell line SK-N-MC. Hydrophilic antioxidants viz., L-ascorbic acid (VitC) and N-acetyl-L-cysteine (l-NAC) had no prote...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Raghuvar Gopal DV,Narkar AA,Badrinath Y,Mishra KP,Joshi DS

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  • Skin absorption of aniline from aqueous solutions in man.

    abstract::The skin absorption of aniline, aniline with 3% water content, and 1 and 2% aqueous aniline solutions was investigated in man. The time of exposure was 30 or 60 min. The absorbed amount of aniline was calculated on the basis of rho-aminophenol excretion in 24-h urine. The rate of aniline absorption from aqueous soluti...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Baranowska-Dutkeiwicz B

    更新日期:1982-03-01 00:00:00

  • Intestinal injury alters tissue distribution and toxicity of ZnO nanoparticles in mice.

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    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Du LJ,Xiang K,Liu JH,Song ZM,Liu Y,Cao A,Wang H

    更新日期:2018-10-01 00:00:00

  • PM2.5 exposure and cold stress exacerbates asthma in mice by increasing histone acetylation in IL-4 gene promoter in CD4+ T cells.

    abstract::Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Zhou J,Geng F,Xu J,Peng L,Ye X,Yang D,Zhao J,Sun Q

    更新日期:2019-11-01 00:00:00

  • Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice.

    abstract::The biomedical application of single-walled carbon nanotubes (SWCNTs), such as drug delivery and cancer treatment, requires a clear understanding of their fate and toxicological profile after intravenous administration. In this study, the long-term accumulation and toxicity of intravenously injected SWCNTs in the main...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Yang ST,Wang X,Jia G,Gu Y,Wang T,Nie H,Ge C,Wang H,Liu Y

    更新日期:2008-10-01 00:00:00

  • Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

    abstract::Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have on...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Wright LK,Lee RB,Vincelli NM,Whalley CE,Lumley LA

    更新日期:2016-01-22 00:00:00

  • 3,4,3',4'-Tetrachlorobiphenyl given to mice prenatally produces long-term decreases in striatal dopamine and receptor binding sites in the caudate nucleus.

    abstract::Pregnant CD-1 mice were given 32 mg/kg of 3,4,3',4'-tetrachlorobiphenyl (TCB) or corn oil vehicle, by gavage, on days 10--16 of gestation. At 1 year of age, the offspring were tested for spontaneous motor activity; the mice were then killed and dopamine (DA) levels and specific DA receptor binding were measured in the...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Agrawal AK,Tilson HA,Bondy SC

    更新日期:1981-03-01 00:00:00

  • Indomethacin induces small intestinal damage and inhibits amitrole-associated thyroid carcinogenesis in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

    abstract::Effects of intestinal damage on thyroid carcinogenesis due to amitrole (AT) were examined in F344 male rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). In experiment 1, rats were provided with diet containing 0.03% AT for 20 weeks after a single subcutaneous injection of DHPN (2800 mg/kg body weight), and...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Imai T,Onose J,Hasumura M,Takizawa T,Hirose M

    更新日期:2006-06-20 00:00:00

  • Polymorphic CYP genes and disease predisposition--what have the studies shown so far?

    abstract::The risk of lung and urinary bladder cancers was reported to be increased in individuals who carried high risk genotypes in either cytochrome P450 (CYP)1A1, CYP2E1 or glutathione S-transferase (GST)M1, and the combined genotype of both CYP1A1 and GSTM1 enzymes have an enhanced tendency of risk to lung cancer more sign...

    journal_title:Toxicology letters

    pub_type: 杂志文章,评审


    authors: Watanabe M

    更新日期:1998-12-28 00:00:00

  • Activation-induced cell death signalling in CD4+ T cells by staphylococcal enterotoxin A.

    abstract::Staphylococcal enterotoxin A (SEA) is a potent stimulator of CD4+ and CD8+ T cells, the immunotoxic action of which remains unclear. We investigated the in vitro effects of SEA on freshly isolated human peripheral blood lymphocytes depleted of CD8+ T cells. Proliferation and flow cytometry analysis indicated that SEA ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Porichis F,Morou A,Baritaki S,Spandidos DA,Krambovitis E

    更新日期:2008-01-04 00:00:00

  • Relationship between oxidative metabolites of hydrazine and hydrazine-induced mutagenicity.

    abstract::Hydrazine (Hz) mutagenicity was observed in a test using Escherichia coli B/r strain, WP2 uvrA and was enhanced by the addition of rat liver microsomal fraction containing a generating system, while the enhanced mutagenicity was diminished by the addition of metyrapone to the microsome-free levels. On the other hand, ...

    journal_title:Toxicology letters

    pub_type: 杂志文章


    authors: Noda A,Ishizawa M,Ohno K,Sendo T,Noda H

    更新日期:1986-05-01 00:00:00