37 research outputs found
A new sighting study for the fixed concentration procedure to allow for gender differences
The fixed concentration procedure (FCP) has been proposed as an alternative to the median lethal
concentration (LC50) test (organisation for economic co-operation and development (OECD) test guideline
[TG] 403) for the assessment of acute inhalation toxicity. The FCP tests animals of a single gender (usually
females) at a number of fixed concentration levels in a sequential fashion. It begins with a sighting study that precedes
the main FCP study and is used to determine the main study starting concentration. In this paper, we propose
a modification to the sighting study and suggest that it should be conducted using both male and female
animals, rather than just animals of a single gender. Statistical analysis demonstrates that, when females are more
sensitive, the new procedure is likely to give the same classification as the original FCP, whereas, if males are more
sensitive, the new procedure is much less likely to lead to incorrect classification into a less toxic category. If
there is no difference in the LC50 for females and males, the new procedure is slightly more likely to classify into
a more stringent class than the original FCP. Overall, these results show that the revised sighting study ensures
gender differences in sensitivity do not significantly impact on the performance of the FCP, supporting its use as
an alternative test method for assessing acute inhalation toxicity
A statistical evaluation of the effects of gender differences in assessment of acute inhalation toxicity
Acute inhalation toxicity of chemicals has conventionally been assessed by the median lethal concentration
(LC50) test (organisation for economic co-operation and development (OECD) TG 403). Two new methods,
the recently adopted acute toxic class method (ATC; OECD TG 436) and a proposed fixed concentration procedure
(FCP), have recently been considered, but statistical evaluations of these methods did not investigate
the influence of differential sensitivity between male and female rats on the outcomes. This paper presents an
analysis of data from the assessment of acute inhalation toxicity for 56 substances. Statistically significant differences
between the LC50 for males and females were found for 16 substances, with greater than 10-fold differences
in the LC50 for two substances. The paper also reports a statistical evaluation of the three test
methods in the presence of unanticipated gender differences. With TG 403, a gender difference leads to a
slightly greater chance of under-classification. This is also the case for the ATC method, but more pronounced
than for TG 403, with misclassification of nearly all substances from Globally Harmonised System (GHS) class 3
into class 4. As the FCP uses females only, if females are more sensitive, the classification is unchanged. If males
are more sensitive, the procedure may lead to under-classification. Additional research on modification of the
FCP is thus proposed
An evaluation of the fixed concentration procedure for assessment of acute inhalation toxicity
Acute inhalation studies are conducted in animals as part of chemical hazard identification and for classification and labelling. Current methods employ death as an endpoint (OECD TG403 and TG436) while the recently approved fixed concentration procedure (FCP) (OECD TG433) uses fewer animals and replaces lethality as an endpoint with evident toxicity. Evident toxicity is the presence of clinical signs that predict that exposure to the next highest concentration will cause severe toxicity or death in most animals. Approval of TG433 was the result of an international initiative, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), which collected data from six laboratories on clinical signs recorded for inhalation studies on 172 substances. This paper summarises previously published data and describes the additional analyses of the dataset that were essential for approval of the TG
Late Oligocene Warming Event in the southern North Sea Basin: benthic foraminifera as paleotemperature proxies
Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use
This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities
An evaluation of the fixed concentration procedure for assessment of acute inhalation toxicity
Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: an international workshop report
Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, “Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements”, explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations