scholarly journals Threshold of Toxicological Concern—An Update for Non-Genotoxic Carcinogens

2021 ◽  
Vol 3 ◽  
Author(s):  
Monika Batke ◽  
Fatemeh Moradi Afrapoli ◽  
Rupert Kellner ◽  
James F. Rathman ◽  
Chihae Yang ◽  
...  
Keyword(s):  
Organic Compounds ◽  
Animal Studies ◽  
Model Averaging ◽  
Threshold Value ◽  
Benchmark Dose ◽  
Oral Exposure ◽  
Genotoxic Carcinogens ◽  
Genotoxic Compounds ◽  
Threshold Of Toxicological Concern ◽  
Dose Levels

The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class, even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumor incidence were compared with no observed effect levels (NOELs) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the Carcinogenicity Potency DataBase (CPDB) as either non-genotoxic or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a dataset of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well-known repositories, such as RepDose, ToxRef, and COSMOS DB. Further, an effective tumor dose (ETD10) was calculated and compared with the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in the region of the fifth percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher but comparable fifth percentile chronic NOEL and BMDL10 values, while the fifth percentile EDT10 value was slightly higher but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non-genotoxic compounds, such as non-genotoxic carcinogens.

scholarly journals Concordance of Transcriptional and Apical Benchmark Dose Levels for Conazole-Induced Liver Effects in Mice

2013 ◽  
Vol 136 (1) ◽  
pp. 205-215 ◽  
Author(s):  
Virunya S. Bhat ◽  
Susan D. Hester ◽  
Stephen Nesnow ◽  
David A. Eastmond
Keyword(s):  
Benchmark Dose ◽  
Dose Levels

SPECIAL REQUIREMENTS FOR TOXICITY TESTING OF ORAL COMPOUNDS ADMINISTERED CONTINUOUSLY OR CYCLICALLY

1974 ◽  
Vol 77 (1_Suppla) ◽  
pp. S387-S408 ◽  
Author(s):  
G. A. Overbeek ◽  
H. W. Hornstra ◽  
E. B. van Julsingha ◽  
J. P. Mumford ◽  
I. Zayed
Keyword(s):  
Side Effects ◽  
Oral Contraceptives ◽  
Predictive Value ◽  
Animal Studies ◽  
Toxicity Testing ◽  
Prolonged Treatment ◽  
Safety Studies ◽  
Short And Long Term ◽  
Dose Levels

ABSTRACT The authors feel that several reasons exist for considering contraceptives as a special class of drugs, which therefore require special safety studies. Apart from the usual short and long term studies, particular attention should be paid to the reversibility of the induced infertility, and to its possible consequences for subsequent offspring. A possible risk of damage to the foetus is partially outweighed by the low risk of pregnancy during the treatment periods with oral contraceptives. The procedures used in the Organon laboratories are briefly described. Principles on which we base the choice of dose levels and the duration of the various studies are discussed. The paucity of available data from toxicity studies in animals has prevented the presentation of a summary allowing an appraisal of the predictive value of the current methods in toxicology. Nevertheless, a few examples are given which demonstrate the need for more predictive methods. The present lack of knowledge on side effects in humans after prolonged treatment with oral contraceptives has created a feeling of uneasiness. This in its turn has resulted in some excessive regulatory requirements for very long term animal studies. In our opinion, the predictive value of these studies is extremely low because of the inadequacy of the available animal models. More value can be attached to the monitoring of side effects in humans and efforts in this direction should be increased. The Organon system of monitoring the side effects of its marketed preparations is briefly described. It is not considered feasible to standardize regulatory toxicity requirements for the time being, which should not prevent us from aiming at reasonable, more generally accepted methods of study.

Bayesian model averaging for benchmark dose estimation

2014 ◽  
Vol 22 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Susan J. Simmons ◽  
Cuixian Chen ◽  
Xiaosong Li ◽  
Yishi Wang ◽  
Walter W. Piegorsch ◽  
...  
Keyword(s):  
Bayesian Model ◽  
Bayesian Model Averaging ◽  
Model Averaging ◽  
Benchmark Dose ◽  
Dose Estimation

scholarly journals Harmful Chemicals in Soil and Risk Assessment of an Abandoned Open Dumpsite in Eastern China

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Ying Huang ◽  
YongXia Li ◽  
Jian Yang ◽  
MinMin Xu ◽  
Bo Sun ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Risk Assessment ◽  
Organic Compounds ◽  
Health Risks ◽  
Ecological Risk ◽  
Eastern China ◽  
Soil Samples ◽  
Oral Exposure ◽  
Inorganic Pollutants ◽  
Boundary Area

The concentrations of pollutants in soil samples collected in and around a dumpsite in Heze, Shandong, China, were investigated, and the potential ecological and health risks of these pollutants were assessed. Seventeen soil samples from five different locations were analysed for pollution characteristics, and the target pollutants included inorganic pollutants and heavy metals as well as volatile organic compounds/semivolatile organic compounds (VOCs/SVOCs). Results showed that the mean concentration level of each pollutant from the interior area was relatively higher than that from the boundary area of the dumpsite. Inorganic pollutants and heavy metals were detected in all of the soil samples. According to potential ecological risk assessment with environmental background values of Shandong as screening values, heavy metals in majority of the samples pose low ecological risk to the ecosystem except Hg. Hg poses a considerable or very high risk because of its high levels of accumulation. In consideration of future land use pattern, human health risks derived from environmental exposure to heavy metals were assessed. Carcinogenic risk and noncarcinogenic hazards for adults are acceptable, while noncarcinogenic hazards for children exceed the safety threshold. The health risks are primarily attributed to oral exposure to As and Cr.

scholarly journals Accurate hematopoietic stem cell frequency estimates by fitting multicell Poisson models substituting to the single-hit Poisson model in limiting dilution transplantation assays

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2472-2475 ◽  
Author(s):  
Thierry Bonnefoix ◽  
Mary Callanan
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Model Averaging ◽  
Poisson Model ◽  
Threshold Value ◽  
Threshold Level ◽  
Hematopoietic Stem ◽  
Gold Standard Method ◽  
Poisson Models ◽  
Limiting Dilution

Abstract Limiting dilution transplantation assay (LDTA) is considered as the gold standard method to assess hematopoietic stem cell (HSC) content. Traditionally, HSC frequency estimates are based on the single-hit Poisson model (SHPM), which posits that one donor HSC is sufficient to generate a progeny of detectable differentiated cells above a threshold value in hosts. However, there is no clear support for this statement, and it is receivable that more than one donor HSC may be necessary to provide detectable reconstitution in hosts above the threshold level for detection, usually 0.5% to 1% of donor-derived cells. To address this hypothesis, we evaluated the ability of a class of multiCell Poisson models (C≥1PMs) to fit to LDTAs. In 7 of the 8 reanalyzed LDTAs, C≥1PMs plausibly compete with the traditional SHPM. Model averaging across the set of plausible models gives 1.32- to 5.88-fold increases in HSC frequencies compared with the SHPM.

scholarly journals Short-Term Toxicity (One-and Ten-Day Gavage) of Barium Chloride in Male and Female Rats

1988 ◽  
Vol 7 (5) ◽  
pp. 675-685 ◽  
Author(s):  
J.F. Borzelleca ◽  
L.W. Condie ◽  
J.L. Egle
Keyword(s):  
Body Weight ◽  
Barium Chloride ◽  
Female Rats ◽  
Oral Exposure ◽  
Short Term ◽  
Kidney Weight ◽  
Male And Female ◽  
Adverse Health Effects ◽  
Male And Female Rats ◽  
Dose Levels

To assess adverse effects that might be caused by an event resulting in high levels of barium in drinking water, rats were gavaged with barium chloride (BaCl2 at dosage levels of 30, 100, and 300 mg/kg in a 1-day study and at 100, 145, 209, and 300 mg/kg for 10 days, and the effects were determined. LD50 values for male and female rats were found to be 419 (352–499) and 408 (342–487) mg/kg BaCl2, respectively. In the 1-day exposure study, decreases in body weight and liver/brain weight ratios and increase in kidney weight as a percentage of body weight appeared to be related to barium ingestion at 300 mg/kg. After 10 days of exposure to barium, survival of females was substantially lower at 300 mg/kg. A reduction in ovaries/brain ratio at 300 mg/kg appeared to be barium-induced. There was a decrease in BUN at 300 mg/kg in males and at all dose levels in females. No other effects were attributed to barium. Histopathological findings were negative in both the 1-and 10-day studies. It is concluded that short-term oral exposure to BaCl2 at doses up to 209 mg/kg produces no significant adverse health effects.

Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8574-8574
Author(s):  
Greg Coffey ◽  
Aradhana Rani ◽  
Andreas Betz ◽  
Yvonne Pak ◽  
Anjali Pandey ◽  
...  
Keyword(s):  
Confidence Interval ◽  
B Cell ◽  
Cell Activation ◽  
Oral Exposure ◽  
Healthy Male ◽  
Single Dose Study ◽  
Healthy Male Volunteers ◽  
Male Volunteers ◽  
Syk Inhibitor ◽  
Dose Levels

8574 Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as FcεRI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a Tmax of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC50of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of FcεRI-mediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.

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