Estimation of Maximum Tolerated Dose for Long‐Term Bioassays from Acute Lethal Dose and Structure by QSAR

Gombar, Viay K.; Enslein, Kurt; Hart, Jeffrey B.; Blake, Benjamin W.; Borgstedt, Harold H.

doi:10.1111/j.1539-6924.1991.tb00636.x

Cited by 16 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this analysis, we use the hypothetical Case D from the previous analysis, which assumes that the chemical of interest tests positive in the mutagenicity test and has a relatively high acute toxicity (LD50 of 60 mg/kg), to illustrate the approach. Test results for this case imply an upper bound value of expected potency since an LD50 of 60 mg/kg correspond to the 5th percentile of LD50 values reported in Gombar et al ( 27 ) Since it represents an upper bound of potential Tier 1 results, the results will represent an upper bound for the risk of cancer given a level of exposure and the benefits from control. For all cases, we evaluate the VOI for exposure‐weighted average doses ranging from 10 −9 to 10 −3 mg/kg/day.…”

Section: Value Of Information To a Constrained Decisionmakermentioning

confidence: 61%

“…Test results of Case A imply a lower bound value of expected potency since the chemical is not mutagenic and an LD50 value of 8,000 mg/kg represents roughly the 95th percentile of LD50 values reported in Gombar et al ( 27 ) Similarly, test results Case D imply an upper bound value of expected potency since an LD50 of 60 mg/kg correspond to the 5th percentile of LD50 values. The expected value of potency for Cases A, B, C, and D are 0.0015, 0.0026, 0.21, and 0.30 (mg/kg/day) −1 , respectively.…”

Section: Value Of Information To a Net Benefit Maximizing Decisionmentioning

confidence: 74%

“…For predicting possible Tier 2 subchronic bioassay results, we use the empirical relationship of LD50 and MTD reported in Gombar et al ( 27 ) for 269 compounds gathered from various databases. From this database, we drop the 12 chemicals where the MTD is greater than LD50, and use @Risk™ version 4.5 to fit distributions to the ratio of MTD to LD50, which yields a lognormal distribution with μ ln K =− 2.3 and σ ln K = 1.4, and produces a good fit with χ 2 statistic of 32 and p ‐value of 0.01.…”

Section: Model Input Valuesmentioning

confidence: 99%

See 2 more Smart Citations

Tiered Chemical Testing: A Value of Information Approach

Yokota¹,

Gray²,

Hammitt³

et al. 2004

Risk Analysis

View full text Add to dashboard Cite

In December 2000 the EPA initiated the Voluntary Children's Chemical Evaluation Program (VCCEP) by asking manufacturers to voluntarily sponsor toxicological testing in a tiered process for 23 chemicals selected for the pilot phase. The tiered nature of the VCCEP pilot program creates the need for clearly defined criteria for determining when information is sufficient to assess the potential risks to children. This raises questions about how to determine the "adequacy" of the existing information and assess the need to undertake efforts to reduce uncertainty (through further testing). This article applies a value of information analysis approach to determine adequacy by modeling how toxicological and exposure data collected through the VCCEP may be used to inform risk management decisions. The analysis demonstrates the importance of information about the exposure level and control costs in making decisions regarding further toxicological testing. This article accounts for the cost of delaying control action and identifies the optimal testing strategy for a constrained decisionmaker who, absent applicable human data, cannot regulate without bioassay data on a specific chemical. It also quantifies the differences in optimal testing strategy for three decision criteria: maximizing societal net benefits, ensuring maximum exposure control while net benefits are positive (i.e., benefits outweigh costs), and controlling to the maximum extent technologically feasible while the lifetime risk of cancer exceeds a specific level of risk. Finally, this article shows the large differences that exist in net benefits between the three criteria for the range of exposure levels where the optimal actions differ.

show abstract

Section: Value Of Information To a Constrained Decisionmakermentioning

confidence: 61%

Section: Value Of Information To a Net Benefit Maximizing Decisionmentioning

confidence: 74%

Section: Model Input Valuesmentioning

confidence: 99%

See 1 more Smart Citation

Tiered Chemical Testing: A Value of Information Approach

Yokota¹,

Gray²,

Hammitt³

et al. 2004

Risk Analysis

View full text Add to dashboard Cite

show abstract

“…In these programs, sets of biophores (analogs of structural alerts) were identified and used for activity predictions. Several more sophisticated fragmentbased expert systems of toxicity assessment -DEREK, 210 TopKat 236 and Rex 237 -have been developed. DEREK is a knowledge-based system operating with human-coded or automatically generated 238 rules concerning toxicophores.…”

Section: Filteringmentioning

confidence: 99%

Fragment Descriptors in SAR/QSAR/QSPR Studies, Molecular Similarity Analysis and in Virtual Screening

Baskin¹,

Varnek²

2008

Chemoinformatics Approaches to Virtual Screening

View full text Add to dashboard Cite

“…Also DEREK and HazardExpert is coded with a number of rules, mainly relating to strong acidic and basic molecular features which may be relevant for eye and skin irritation study [37]. TOPKAT and MultiCASE has its models and DEREK have some rules related to organ toxicity [39,40]. There are limited number of models in this area involving regulatory data.…”

Section: Brief Overview and Application Of Toxicoinformatics Softwaresmentioning

confidence: 99%

Computer-Assisted Methods in Chemical Toxicity Prediction

Mohan

Gandhi²,

Garg³

et al. 2007

MRMC

View full text Add to dashboard Cite

In Silico predictive ADME/Tox screening of compounds is one of the hottest areas in drug discovery. To provide predictions of compound drug-like characteristics early in modern drug-discovery decision making, computational technologies have been widely accepted to develop rapid high throughput in silico ADMET analysis. It is widely perceived that the early screening of chemical entities can significantly reduce the expensive costs associated with late stage failures of drugs due to poor ADME/Tox properties. Drug toxic effects are broadly defined to include toxicity, mutagenicity, carcinogenicity, teratogenicity, neurotoxicity and immunotoxicity. Toxicity prediction techniques and structure-activity relationships relies on the accurate estimation and representation of physico-chemical and toxicological properties. This review highlights some of the freely and commercially available softwares for toxicity predictions. The information content can be utilized as a guide for the scientists involved in the drug discovery arena.

show abstract

Estimation of Maximum Tolerated Dose for Long‐Term Bioassays from Acute Lethal Dose and Structure by QSAR

Cited by 16 publications

References 19 publications

Tiered Chemical Testing: A Value of Information Approach

Tiered Chemical Testing: A Value of Information Approach

Fragment Descriptors in SAR/QSAR/QSPR Studies, Molecular Similarity Analysis and in Virtual Screening

Computer-Assisted Methods in Chemical Toxicity Prediction

Contact Info

Product

Resources

About