Advancing In Vitro–In Vivo Extrapolations of Mechanism-Specific Toxicity Data Through Toxicokinetic Modeling

2016 ◽  
pp. 293-317 ◽  
Author(s):  
Markus Brinkmann ◽  
Thomas G. Preuss ◽  
Henner Hollert
Keyword(s):  
Toxicity Data

scholarly journals Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

2016 ◽  
Vol 91 (2) ◽  
pp. 865-883 ◽  
Author(s):  
Christoph Thiel ◽  
Henrik Cordes ◽  
Isabel Conde ◽  
José Vicente Castell ◽  
Lars Mathias Blank ◽  
...  
Keyword(s):  
Drug Response ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Model Based

The Necessity of Biokinetic Information in the Interpretation of In Vitro Toxicity Data

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 85-91 ◽  
Author(s):  
Bas J. Blaauboer
Keyword(s):  
Critical Concentration ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Data ◽  
Hazard And Risk ◽  
Hazard And Risk Assessment ◽  
Critical Site ◽  
Dose Metric

Data derived from in vitro toxicity studies are not directly applicable in an assessment of the toxicity of compounds in intact organisms. The major limitation is the lack of knowledge of biokinetic behaviour in vivo. Since the toxicity of a compound will be determined by the critical concentration (or other dose metric) of the critical compound (or a metabolite thereof) at the critical site of toxic action, biokinetic behaviour must be taken into account. Possibilities of biokinetic modelling on the basis of in vitro and other non-animal data are discussed, and the application of the results in hazard and risk-assessment schedules is considered.

Final Report on the Safety Assessment of 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Chloro-2-Aminophenol1

2004 ◽  
Vol 23 (2_suppl) ◽  
pp. 1-22 ◽  
Keyword(s):  
Test Data ◽  
Expert Panel ◽  
Skin Irritation ◽  
Percutaneous Penetration ◽  
Final Report ◽  
Toxicity Data ◽  
Hair Dyes ◽  
Animal Skin

Each of these ingredients function as hair colorants. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol are identified as oxidative hair dyes, that is, they are combined with an oxidizing agent before being applied to the hair. 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, and 5-Amino-4-Chloro-o-Cresol are used in oxidative hair dyes, but it is not known if they are also used in nonoxidative (semipermanent) hair dyes. No toxicologically significant impurities are present with these two ingredients. To supplement the safety test data on these ingredients, available data on related ingredients (4-amino-2-hydroxytoluene and p-, m-, and o-aminophenol) previously found safe as used by the Cosmetic Ingredient Review (CIR) Expert Panel were summarized. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol do not absorb significant ultraviolet radiation in the UVB region and none in the UVA region, although 4-Amino-m-Cresol had a symmetrical UV absorption peak at 300 nm. Percutaneous penetration of 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol alone was significant, but when combined with oxidative developer, skin absorption was extremely low. Both of these dyes are excreted rapidly via the urine. Repeated exposure of animal skin to 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol failed to produce any cumulative irritation and single exposures up to 10% were not irritating to animal skin. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol combined with oxidizer were not sensitizers in guinea pig maximization tests. Ocular irritation resulted from exposure of animals to undiluted 5-Amino-4-Chloro-o-Cresol, but not to a 5% solution. Only minor irritation was observed with 5% 5-Amino-6-Chloro-o-Cresol. Subchronic toxicity testing in animals using 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Amino-m-Cresol did not yield any adverse reactions. 6-Amino-m-Cresol and 4-Amino-m-Cresol were generally not mutagenic in in vitro and in vivo tests. Exposure to 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, 6-Amino-m-Cresol and 4-Amino-m-Cresol from cosmetics were several orders of magnitude below developmental toxicity no-observed-adverse-effect levels (NOAELs). Although irritation data on several ingredients are absent, products containing these ingredients must include a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure would identify individuals who would have an adverse reaction and allow them to avoid significant exposures. These compounds, when tested alone, are moderate skin sensitizers, but when combined with the developer, these ingredients are not sensitizers in animal tests. This information, coupled with the available animal test data, supports the safety of these ingredients in oxidative hair dyes. In the absence of systemic toxicity data, however, the available data are insufficient to support the safety of 6-Amino-o-Cresol and 4-Chloro-2-Aminophenol in semipermanent hair dyes. The types of data required for these two ingredients for this use include (1) physical and chemical properties, including the octanol/water partition coefficient; (2) impurities data, especially regarding the presence of m-cresol, other organic molecules, and heavy metals; (3) data demonstrating that the metabolism is similar to that of 4-amino-2-hydroxytoluene and/or p-, m-, and o-aminophenol, or 28-day dermal toxicity with histopathology, dermal reproductive toxicity data, and an in vitro genotoxicity study for 6-Amino-o-Cresol and one genotoxicity study in a mammalian system; if positive, a 2-year dermal carcinogenicity study using National Toxicology Program methods may be needed.

MEIC Evaluation of Acute Systemic Toxicity

1998 ◽  
Vol 26 (1_suppl) ◽  
pp. 93-129 ◽  
Author(s):  
Cecilia Clemedson ◽  
Frank A. Barile ◽  
Barbro Ekwall ◽  
Maria José Gómez-Lechón ◽  
Tony Hall ◽  
...  
Keyword(s):  
Cell Lines ◽  
Primary Cultures ◽  
Toxicity Testing ◽  
Preceding Paper ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Animal Cells ◽  
Basal Cytotoxicity

Results from tests on the first 30 MEIC reference chemicals in 16 different systems are presented as a prerequisite to the subsequent in vitro/in vivo comparisons of acute toxicity data, i.e. the final MEIC evaluation of all test results of the study. The study is a supplement to the previously published results from 68 methods (including methods 45B and 46B [old numbers]) used to test the same set of chemicals. The strategies and methods of the preceding paper were employed to enable a comparative cytotoxicity analysis of the results from these 68 methods and from the 16 new methods to be made. Principal components analysis (PCA) of 82 assays demonstrated a dominating first component which described as much as 83% of the variance in the toxicity data. This remarkable similarity of all toxicity data was the main finding of the present study, and confirmed the results of the previous study with a less-extensive database. Also, the influence on the general variability of results of several key methodological factors was evaluated by analysis of selected sets of data, including linear regression of the results of pairs of methods, which were similar in all respects except for the factor under analysis. This analysis of the same 82 assays as before also confirmed previous results from the 68 assay database: a) the toxicities of a third of the chemicals increased considerably with exposure time; b) in general, cytotoxicity for human cells was well predicted by cytotoxicity tests with animal cells; c) this prediction was poor for two chemicals, i.e. digoxin and malathion; d) prediction of human cytotoxicity by ecotoxicological tests was only fairly good; e) 25 comparisons of similar assays employing different cell lines showed strikingly similar toxicities (mean R2 = 0.86); f) 22 comparisons of similar pairs of assays employing different primary cultures and cell lines also revealed similar toxicities (mean R2 = 0.79); and g) 15 comparisons of similar assays with different growth/viability endpoint measurements demonstrated strikingly similar toxicities (mean R2 = 0.89). Results b, e, f and g must be the main causes of the general similarity of results, while results a, c and d, together with other factors, could explain the 20% dissimilarity. These findings support the basal cytotoxicity concept and may assist in guiding and refining in vitro toxicity testing in the future.

scholarly journals The Use of In Vitro Toxicity Data and Physiologically Based Kinetic Modeling to Predict Dose-Response Curves for In Vivo Developmental Toxicity of Glycol Ethers in Rat and Man

2010 ◽  
Vol 118 (2) ◽  
pp. 470-484 ◽  
Author(s):  
Jochem Louisse ◽  
Esther de Jong ◽  
Johannes J. M. van de Sandt ◽  
Bas J. Blaauboer ◽  
Ruud A. Woutersen ◽  
...  
Keyword(s):  
Kinetic Modeling ◽  
Dose Response ◽  
Developmental Toxicity ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Glycol Ethers ◽  
Response Curves ◽  
Physiologically Based

scholarly journals Formation of Nudicaulins In Vivo and In Vitro and the Biomimetic Synthesis and Bioactivity of O-Methylated Nudicaulin Derivatives

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3357 ◽  
Author(s):  
Bettina Dudek ◽  
Florian Schnurrer ◽  
Hans-Martin Dahse ◽  
Christian Paetz ◽  
Anne-Christin Warskulat ◽  
...  
Keyword(s):  
Biomimetic Synthesis ◽  
Toxicity Data ◽  
Cell Toxicity ◽  
Pharmacological Activities ◽  
Synthetic Procedure ◽  
Ph Dependent ◽  
Flower Pigments ◽  
New Compounds

Nudicaulins are yellow flower pigments accounting for the color of the petals of Papaver nudicaule (Papaveraceae). These glucosidic compounds belong to the small group of indole/flavonoid hybrid alkaloids. Here we describe in vivo and in vitro experiments which substantiate the strongly pH-dependent conversion of pelargonidin glucosides to nudicaulins as the final biosynthetic step of these alkaloids. Furthermore, we report the first synthesis of nudicaulin aglycon derivatives, starting with quercetin and ending up at the biomimetic fusion of a permethylated anthocyanidin with indole. A small library of nudicaulin derivatives with differently substituted indole units was prepared, and the antimicrobial, antiproliferative and cell toxicity data of the new compounds were determined. The synthetic procedure is considered suitable for preparing nudicaulin derivatives which are structurally modified in the indole and/or the polyphenolic part of the molecule and may have optimized pharmacological activities.

PLATOX – In vitro and in vivo investigations (28-day inhalation) to generate valid toxicity data for risk assessment of carbon-based nanoplatelets

2017 ◽  
Vol 280 ◽  
pp. S146-S147
Author(s):  
Otto Creutzenberg ◽  
Christina Ziemann ◽  
Helena Oliveira ◽  
Lucian farcal ◽  
Sabina Burla
Keyword(s):  
Risk Assessment ◽  
Toxicity Data ◽  
Carbon Based

Experimental approaches to the chemotherapy of Trichomoniasis

Parasitology ◽  
1963 ◽  
Vol 53 (1-2) ◽  
pp. 303-320 ◽  
Author(s):  
J. F. Ryley ◽  
G. J. Stacey
Keyword(s):  
Clinical Trial ◽  
Technical Assistance ◽  
Toxicity Data ◽  
Vaginal Infections ◽  
Experimental Systems ◽  
Experimental Approaches ◽  
Clinical Trial Results ◽  
Serum And Urine

1. Experimental systems are described for studying the interaction of compounds with various species of trichomonad. In vitro systems have been used to study the effects of compounds on trichomonads growing in culture and to determine the speed of action of compounds on non-dividing populations. In vivo experiments have utilized vaginal infections in hamsters and subcutaneous, intraperitoneal, intra-muscular and caecal infections in mice. In vitro assays have also been carried out on serum and urine obtained from non-infected rats or monkeys dosed with compounds showing in vitro activity.2. The types of activity which can be obtained experimentally are illustrated by reference to a number of local remedies already available and to representatives of a number of chemical types, notably acridines, quinoxaline N-oxides, anthrapyrimidines, nitrofurans, thiazoles, imidazoles and pyrazoles.We thank Dr R. F. Jennison and Mr H. Francis for clinical trial results, Drs J. K. Landquist, G. V. McHattie and D. Richardson for synthesis of some of the compounds mentioned, Dr G. E. Paget for toxicity data, Dr W. M. Duncan for data on the metabolism of 5667, Dr J. M. Pryce for pK determinations and Mrs M. Ryley, P. Ward, A. Fletcher, D. Wood and Miss V. Rowe for technical assistance at various stages in the work.

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