Benchmark dose analysis of multiple genotoxicity endpoints in gpt delta mice exposed to aristolochic acid I

Mutagenesis ◽  
2020 ◽  
Author(s):  
Ruixue Chen ◽  
Xinyue You ◽  
Yiyi Cao ◽  
Kenichi Masumura ◽  
Tomoko Ando ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Carcinogenic Risk ◽  
Dna Adduct ◽  
Benchmark Dose ◽  
Multiple Endpoints ◽  
Regulatory Decision ◽  
Global Health Issue ◽  
Gpt Delta

Abstract As the carcinogenic risk of herbs containing aristolochic acids (AAs) is a global health issue, quantitative evaluation of toxicity is needed for the regulatory decision-making and risk assessment of AAs. In this study, we selected AA I (AAI), the most abundant and representative compound in AAs, to treat transgenic gpt delta mice at six gradient doses ranging from 0.125 to 4 mg/kg/day for 28 days. AAI-DNA adduct frequencies and gpt gene mutation frequencies (MFs) in the kidney, as well as Pig-a gene MFs and micronucleated reticulocytes (MN-RETs) frequencies in peripheral blood, were monitored. The dose–response (DR) relationship data for these in vivo genotoxicity endpoints were quantitatively evaluated using an advanced benchmark dose (BMD) approach with different critical effect sizes (CESs; i.e., BMD5, BMD10, BMD50 and BMD100). The results showed that the AAI-DNA adduct frequencies, gpt MFs and the MN-RETs presented good DR relationship to the administrated doses, and the corresponding BMDL100 (the lower 90% confidence interval of the BMD100) values were 0.017, 0.509 and 3.9 mg/kg/day, respectively. No positive responses were observed in the Pig-a MFs due to bone marrow suppression caused by AAI. Overall, we quantitatively evaluated the genotoxicity of AAI at low doses for multiple endpoints for the first time. Comparisons of BMD100 values across different endpoints provide a basis for the risk assessment and regulatory decision-making of AAs and are also valuable for understanding the genotoxicity mechanism of AAs.

The Extension of Molecular and Computational Information to Risk Assessment and Regulatory Decision Making*

2006 ◽  
pp. 151-180 ◽  
Author(s):  
James Bus ◽  
Richard Canady ◽  
Tracy Collier ◽  
J William Owens ◽  
Syril Pettit ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Regulatory Decision

Use of Percutaneous Absorption Data in Risk Assessment

1989 ◽  
Vol 8 (5) ◽  
pp. 815-827 ◽  
Author(s):  
C. A. Franklin ◽  
D. A. Somers ◽  
I. Chu
Keyword(s):  
Risk Assessment ◽  
Percutaneous Absorption ◽  
Dermal Absorption ◽  
In Vivo Studies ◽  
Absorption Data ◽  
Regulatory Decision ◽  
Dermal Penetration ◽  
High Doses

Assessment of risks to humans associated with the use of chemicals requires knowledge of the hazard (toxicity) of the chemical and level of human exposure. Hazard assessment is often based on animal bioassays and quantitative exposure estimates of dermal exposure obtained from studies monitoring workers. Because human skin is an effective barrier to many chemicals, it cannot be assumed that the deposited dose is equivalent to the systemic dose. However, an estimate of systemic dose may be derived by multiplying the deposited dose by the percentage of percutaneous uptake. This correction can have major impact on the regulatory decision, because the adjusted dose used in the risk calculation may be reduced significantly, especially at high doses, when the uptake is not linearly proportional to the exposure. It is therefore important that the dermal absorption value be accurate. As outlined in this paper, numerous factors can affect percutaneous absorption. Nevertheless, many regulatory agencies will consider the use of percutaneous absorption data derived from in vivo studies to adjust the dermally deposited dose to that delivered systemically. Numerous issues must be resolved before in vitro dermal penetration studies can be used for risk assessment.

The use of risk assessment in regulatory decision making: Time for a review

1981 ◽  
Vol 1 (3) ◽  
pp. 264-276 ◽  
Author(s):  
John T. Barr ◽  
Donald H. Hughes ◽  
Robert C. Barnard
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Regulatory Decision

Initiating and Managing Risk Assessments within a Risk Analysis Framework: FDA/CFSAN'S Practical Approach

2004 ◽  
Vol 67 (9) ◽  
pp. 2058-2062 ◽  
Author(s):  
ROBERT L. BUCHANAN ◽  
SHERRI DENNIS ◽  
MARIANNE MILIOTIS
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Risk Management ◽  
Risk Analysis ◽  
Risk Assessments ◽  
Analysis Framework ◽  
Regulatory Decision ◽  
Managing Risk ◽  
Risk Managers ◽  
The U.S

Management of risk analysis involves the integration and coordination of activities associated with risk assessment, risk management, and risk communication. Risk analysis is used to guide regulatory decision making, including trade decisions at national and international levels. The U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition (CFSAN) formed a working group to evaluate and improve the quality and consistency of major risk assessments conducted by the Center. Drawing on risk analysis experiences, CFSAN developed a practical framework for initiating and managing risk assessments, including addressing issues related to (i) commissioning a risk assessment, (ii) interactions between risk managers and risk assessors, and (iii) peer review.

Risk assessment and regulatory decision making

1981 ◽  
Vol 19 ◽  
pp. 549-560 ◽  
Author(s):  
I.C. Munro ◽  
D.R. Krewski
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Regulatory Decision

Implementing a globally harmonized risk assessment‐based approach for regulatory decision‐making of crop protection products

2020 ◽  
Vol 76 (10) ◽  
pp. 3311-3315 ◽  
Author(s):  
Douglas C Wolf ◽  
Manoj Aggarwal ◽  
Michael Battalora ◽  
Ann Blacker ◽  
Shadia I Catalano ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Crop Protection ◽  
Regulatory Decision

Drug Safety, Pharmacoepidemiology, and Regulatory Decision Making

1988 ◽  
Vol 22 (4) ◽  
pp. 336-344 ◽  
Author(s):  
Robert C. Nelson
Keyword(s):  
Risk Assessment ◽  
Decision Making ◽  
Conceptual Framework ◽  
Knowledge Base ◽  
Case Studies ◽  
Drug Safety ◽  
Research Question ◽  
Regulatory Decision ◽  
Risk Manager ◽  
Interpretive Framework

The safety or risk assessment of a pharmacotherapeutic agent begins early in its development and continues throughout its use cycle. The practice of pharmacoepidemiology is the art of using the sciences and the tools of science to generate information about pharmaceutical outcomes, including associated risks, in the postmarketing environment. A pharmacoepidemiologist must be capable of functioning with a matrix constructed of three components: a knowledge base, a conceptual framework, and an interpretive framework. From this perspective one can establish surveillance schemes, or understand a posed research question, select strategies, apply methodologies, and interpret the results of purposeful investigations. When conveyed to the risk manager, appropriately interpreted results of a properly conducted risk assessment can be used in regulatory decision making. Seven case studies are presented as examples of this approach.

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