The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Mark E Arnold - One of the best experts on this subject based on the ideXlab platform.

  • Bioanalysis of propylparaben and p-hydroxybenzoic acid, and their sulfate conjugates in rat plasma by liquid chromatography-tandem mass spectrometry.
    Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2013
    Co-Authors: Yue Zhao, Guowen Liu, Hongwu Shen, Jim X Shen, Anne-françoise Aubry, Lakshmi Sivaraman, Mark E Arnold
    Abstract:

    Two rugged liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for the determination of propylparaben, its major metabolite, p-hydroxybenzoic acid (pHBA), and their sulfate conjugates have been developed and validated in citric acid-treated rat plasma. To prevent propylparaben being hydrolyzed to pHBA ex vivo, rat plasma was first treated with citric acid; then collected and processed at a reduced temperature (ice bath). Stable isotope labeled internal standards, d4-propylparaben, (13)C6-pHBA, and the d4-labeled internal standards of their sulfate conjugates were used in the methods. The analytes were extracted from the matrix using protein precipitation, followed by chromatographic separation on a Waters ACQUITY UPLC HSS T3 column. Quantification using negative ion electrospray was performed on a Sciex API 4000 mass spectrometer. The analytical ranges were established from 2.00 to 200 ng/mL for propylparaben, 50.0-5000 ng/mL for pHBA, 50.0-10,000 ng/mL for the sulfate conjugate of propylparaben (SPP) and 200-40,000 ng/mL for the sulfate conjugate of pHBA (SHBA). Inter- and intra-run precision for the quality control samples were less than 5.3% and 4.4% for all analytes; and the overall accuracy was within ±5.7% of the nominal values. The validated bioanalytical methods demonstrated excellent sensitivity, specificity, accuracy and precision and were successfully applied to a rat toxicology study under the regulations of Good Laboratory Practices (GLP). Strategies have been developed and applied toward overcoming the challenges related to analyte stability, and environmental and endogenous background.

R E Brackett - One of the best experts on this subject based on the ideXlab platform.

  • Good Laboratory Practices becker et al respond
    Environmental Health Perspectives, 2010
    Co-Authors: Richard A Becker, Erik R Janus, Russell White, Francis H Kruszewski, R E Brackett
    Abstract:

    We appreciate the dialogue stimulated by our letter to the editor (Becker et al. 2009). Our intent was to respond only to Myers et al. (2009) regarding the purpose and function of Good Laboratory Practices (GLP) for weighting reliability of studies. Tyl (2009), in response to Myers et al. (2009), provided extensive point-by-point discussion of the specific studies. In his letter, Tweedale implies that we argued to a priori exclude academic, non-GLP studies from risk assessments. To the contrary, we clearly stated that “[e]ach study, GLP and non-GLP, should be evaluated and weighed in accordance with fundamental scientific principles” (Becker et al. 2009). We fully agree with Tweedale that sources of funding should be disclosed, that researchers should “make their methods and data more freely available,” and more industry-supported studies should be published in scientific journals. With respect to bias, Maurissen et al. (2005) and Barrow and Conrad (2006) discussed the spectrum of mechanisms in place to ensure the integrity of industry-sponsored research. Ultimately, all scientific research must stand on its merits. However, it is unscientific to eliminate or devalue any study based solely on the organization that conducted the study, the affiliation of an investigator, or the source of funding. The Society of Toxicology (2008) has stated this principle quite clearly: “[r]esearch should be judged on the basis of scientific merit, without regard for the funding source or where the studies are conducted (e.g., academia, government, or industry).” Moreover, we did not seek to call into question scientific journal peer review per se, but instead to point out that whereas all study records and data from GLP investigations are available to regulatory agencies, rarely are such details made available as part of a peer-reviewed article published in a scientific journal. The point we wish to emphasize is that typical regulatory safety assessment studies conducted in accordance with GLP a) must follow agency test guidelines to assure use of relevant test systems, sufficient and applicable dosing protocols, and adequate dose groups and sizes, and b) must evaluate specific end points that regulatory organizations consider validated. Further, such GLP studies submitted to regulatory agencies generally include both a full study report and all raw data. This level of scientific rigor and the extensive data of a GLP study allow a regulatory agency to conduct a comprehensive review and to reach a fully independent conclusion. For these reasons, greater weight and confidence are generally afforded to GLP studies. Now, with the increasingly common practice of journals providing access to supplemental data, there are expanded opportunities for researchers to disseminate actual study data; this should facilitate independent evaluation by regulatory agencies. As scientists specializing in regulatory safety evaluations, we have extensive experience in interpreting chemical toxicity studies from government, academia, and private- sector laboratories. In conducting chemical risk assessments, we believe that scientists from all sectors should support the use of objective criteria for determining data quality and study reliability (Schneider et al. 2009) coupled with a structured evaluative framework, such as that of the World Health Organization International Programme on Chemical Safety (Boobis et al. 2006, 2008), to provide a systematic approach for assessing the overall weight of the evidence for observed effects and the postulated mode of action. In this manner, data from Laboratory experiments, epidemiological investigations, and cutting-edge mechanistic research from all relevant studies—GLP and non-GLP—and from all investigators, regardless of affiliation or funding source, can be comprehensively reviewed, given appropriate weight, and integrated in a manner that provides a robust, biologically plausible understanding of the potential hazards and risks that exposures to a substance could pose.

  • Good Laboratory Practices and safety assessments
    Environmental Health Perspectives, 2009
    Co-Authors: Richard A Becker, Erik R Janus, Russell White, Francis H Kruszewski, R E Brackett
    Abstract:

    Having confidence in scientific procedures and data is the sine qua non for determining the safety of chemicals and chemical products. For decisions of safety, there must be rigorous and thorough application of fundamental scientific Practices, irrespective of the purpose of the study and where it is conducted—academic, industry, or a contract Laboratory. Investigations must be designed and conducted by experts; whenever possible, standardized and validated test methods and test systems should be used, test devices and instruments must be appropriately calibrated and their accuracy assured, and, most important, all of the data, including raw Laboratory records, should be available for independent review. Good Laboratory Practice (GLP) requirements, based on these fundamental scientific principles and Practices, are indispensable for providing scientific confidence in studies conducted for chemical safety determinations. These reasons explain why government agencies worldwide require GLP compliance, and why it is entirely appropriate for greater weight to be given to GLP studies than non-GLP studies that are only available as articles in scientific journals. In their commentary Myers et al. (2009) argued that noncompliance with GLP should not be used as the sole criterion for excluding studies from consideration in regulatory decision-making. We agree that GLP should not be the sole criterion, but we strenuously disagree with the authors’ mischaracterization of the purpose and function of GLP and with their conclusion that GLP has no utility for weighting the reliability of studies. Evaluating the safety of any substance should include review of all relevant studies utilizing a systematic weight-of-evidence framework. Although not all studies that are useful for hazard characterization and risk assessment may be amenable to GLP (e.g., epidemiology and mechanistic studies, studies conducted before the acceptance of current GLP), this does not obviate their consideration. Each study, GLP and non-GLP, should be evaluated and weighed in accordance with fundamental scientific principles. Factors to be evaluated include a) verification of measurement methods and data; b ) control of experimental variables that could affect measurements; c ) corroboration among studies; d) power (both statistical and biological); e) universality of the effects in validated test systems using relevant animal strains and appropriate routes of exposure; f) biological plausibility of results; and g) uniformity among substances with similar attributes and effects. Regulatory agencies [Food and Drug Administration (FDA) and U. S. Environmental Protection Agency (EPA)] and the National Toxicology Program (NTP) require studies to be conducted in accordance with GLP (FDA 2005; NTP 2006; U.S. EPA 2007a, 2007b), and the Organisation for Economic Co-operation and Development (OECD) GLP principles (OECD 1998) apply to all OECD member countries. Academic basic research is very different from regulatory research and testing. Academic research focuses on developing and evaluating new hypotheses, on creating novel methods, and on discovering new findings. Academic research is open to wide interpretation and may require significant additional studies to clarify and determine whether and how broadly the results apply. Although novel techniques and discoveries of academic investigations stimulate further research, they must also stand up to the scientific method: hypothesis formulation, hypothesis testing, and validation by independent replication. Independent replication provides critical information on the strength of the hypothesis and reliability of test methods. Inconsistent results can arise from use of novel techniques, different test systems, uncertainty and differences in test chemical composition and purity, and a myriad of other factors. These facts, in conjunction with the more limited availability of actual data in most journal publications, means regulatory agencies can face significant challenges in confirming the quality, performance, or data integrity of results obtained solely from information available from a typical article in peer-reviewed journals. Whereas all study records and data from GLP investigations are available to agencies, rarely, if ever, are such details made available as part of the peer-review process for publishing a manuscript in a scientific journal. This can limit the ability of an agency to independently evaluate conclusions or to conduct alternative analyses of the data. The challenges faced by the peer-review procedures of journals have been recently highlighted (Nature 2006), and it has been pointed out that “…scientists understand that peer review per se provides only a minimal assurance of quality, and that the public conception of peer review as a stamp of authentication is far from the truth” (Jennings 2006). Journal peer review relies on summarization of experimental procedures and results, and does not include examination of Laboratory study records or raw data. The purpose for journal peer review is to judge whether the study has been conducted and reported according to internationally recognized, general scientific standards and whether the study meets the interest level for dissemination to scientific community. It is not designed to provide assurance of accuracy or to recalculate raw data, and it does not provide an opportunity for independent audit of the study. Myers et al. (2009) failed to clearly make these distinctions. Relevant internationally agreed test methods are used by industry to generate toxicity data for safety determinations by regulatory agencies. Incorporation of GLP in these Laboratory tests assures that written protocols and standard operating procedures for each study component are developed and carefully and completely followed. GLP also requires meticulous adherence to dosing techniques; the use of adequate group sizes to allow meaningful statistical analysis; characterization (identity, purity, concentration) of test and control substances, including dosing solutions; detailed recording of study measurements and data; and collection of all raw Laboratory data in a manner that can be retained and made available for regulatory agencies to audit and reach independent conclusions. Quality control procedures, quality assurance reviews, and facility inspections are also used to monitor and enforce GLP compliance. The relevance, reliability, sensitivity, and specificity of most test methods required of industry by regulatory agencies are well understood because they have been subjected to extensive, round-robin validation programs conducted in numerous laboratories throughout the world. This high level of scientific rigor, in conjunction with the detailed processes of GLP, provides regulatory agencies increased confidence in both the relevance and quality of GLP scientific studies for safety decisions, and it is the reason it is wholly appropriate in regulatory decision making for greater weight and confidence to be afforded to studies conducted in accordance with GLP.

Thomas W Jones - One of the best experts on this subject based on the ideXlab platform.

  • regulatory forum opinion piece use and utility of animal models of disease for nonclinical safety assessment a pharmaceutical industry survey
    Toxicologic Pathology, 2017
    Co-Authors: Sherry J Morgan, Jessica Couch, Peggy Guzziepeck, Douglas A Keller, Ray Kemper, Monicah A Otieno, Robert J Schulingkamp, Thomas W Jones
    Abstract:

    An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current Practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities.

Christoph Muller - One of the best experts on this subject based on the ideXlab platform.

  • comparison of turbulent flow chromatography with automated solid phase extraction in 96 well plates and liquid liquid extraction used as plasma sample preparation techniques for liquid chromatography tandem mass spectrometry
    Journal of Chromatography A, 1999
    Co-Authors: Dieter Zimmer, Volker Pickard, Waldemar Czembor, Christoph Muller
    Abstract:

    Turbulent flow chromatography (TFC) combined with the high selectivity and sensitivity of tandem mass spectrometry (MS–MS) is a new technique for the fast direct analysis of drugs from crude plasma. TFC in the 96-well plate format reduces significantly the time required for sample clean-up in the Laboratory. For example, for 100 samples the workload for a technician is reduced from about 8 h by a manual liquid–liquid extraction (LLE) assay to about 1 h in the case of TFC. Sample clean-up and analysis are performed on-line on the same column. Similar chromatographic performance and validation results were achieved using HTLC Turbo-C18 columns (Cohesive Technologies) and Oasis HLB extraction columns (Waters). One 96-well plate with 96 plasma samples is analyzed within 5.25 h, corresponding to 3.3 min per sample. Compared to this LLE and analysis of 96 samples takes about 16 h. Two structurally different and highly protein bound compounds, drug A and drug B, were analyzed under identical TFC conditions and the assays were fully validated for the application to toxicokinetics studies (compliant with Good Laboratory Practices – GLP). The limit of quantitation was 1.00 μg/l and the linear working range covered three orders of magnitude for both drugs. In the case of drug A the quality of analysis by TFC was similar to the reference LLE assay and slightly better than automated solid-phase extraction in 96-well plates. The accuracy was −3.1 to 6.7% and the precision was 3.1 to 6.8% in the case of drug A determined for dog plasma by TFC–MS–MS. For drug B the accuracy was −3.7 to 3.5% and the precision was 1.6 to 5.4% for rat plasma, which is even slightly better than what was achieved with the validated protein precipitation assay.

John Peterson Myers - One of the best experts on this subject based on the ideXlab platform.

  • Good Laboratory Practices are not synonymous with Good scientific Practices, accurate reporting, or valid data.
    Environmental health perspectives, 2010
    Co-Authors: Frederick S. Vom Saal, John Peterson Myers
    Abstract:

    In her commentary, Tyl (2009) responded to our criticism (Myers et al. 2009) of her bisphenol A (BPA) research (Tyl et al. 2008), and she defended the reliance on Good Laboratory Practices (GLP) in animal studies concerning risks posed by chemicals. Her commentary, however, provides additional evidence that her research on BPA is flawed and that GLP can be unreliable. The key evidence can be found in her treatment of the effect of BPA on prostate weight (Tyl et al. 2008). This effect is important because Tyl’s data on adult prostate in mice has been used by the chemical industry—which has funded all of Tyl’s research on BPA—and the Food and Drug Administration (FDA) to conclude that BPA has no effect at low doses. Indeed, Tyl argued that the weight of the evidence supports her findings that BPA is safe (all industry-funded studies report no low-dose effects of BPA). In contrast, > 200 studies in experimental animals, all funded by government agencies, have reported significant effects of BPA at low doses that are relevant to human and ecologic exposures (vom Saal et al. 2007). We (Myers et al. 2009) concluded that prostate weights reported by Tyl et al. (2008) were abnormally high in control males, suggesting either that the dissections were done improperly, that control animals were exposed to a contaminating estrogen, or that their prostates were diseased. This would render the results invalid and therefore inappropriate to use in assessing BPA safety. It would also provide insights as to why, despite many other studies showing adverse effects of exposure to BPA at low doses (vom Saal et al. 2007), Tyl et al. (2008) detected none. To counter this criticism, Tyl (2009) presented a table (her Table 2) of mouse prostate weights from other laboratories. The data she presented in fact show that no other Laboratory measuring prostate weight in mice has reported mean weights as high as those reported by Tyl et al. (2008), except in old male mice with diseased prostates. Tyl’s table cites data from research published by Heindel et al. (1995) previously conducted at her own institution, Research Triangle Institute, although she did not acknowledge this. The mean prostate weight reported by Heindel et al. (1995) for 16- to 17-week-old CD-1 male mice was 48 mg, which is similar to most other findings, but contrasts sharply with Tyl’s mean prostate weights of 74 mg for the F1 males in her BPA study (these males were identified in Table 1 of Tyl’s commentary as being examined at 18 weeks of age). Table 2 of Tyl (2009) also includes data from a publication by Morrissey et al. (1988) showing a mean prostate weight of 58 mg in 23-week-old CD-1 mice. However, this study involved comparing data from two laboratories, and Tyl omitted from her table the data from the second Laboratory that reported a mean prostate weight of 35 mg in 23-week-old CD-1 males. Morrissey et al. (1988) observed that the Laboratory reporting the mean of 58 mg also had a higher standard deviation and lower statistical sensitivity than the Laboratory reporting the 35 mg mean prostate weight. In studies in which prostate weight is high, such as that of Tyl et al. (2008), the findings are suspect in that the abnormally high prostate weight data show a poor relationship to other male reproductive organs (Morrissey et al. 1988). This strongly suggests that nonprostatic tissue has been included when prostate weights are abnormally high in the absence of disease. Tyl’s discussion of prostate weight effects also suggests that studies identified as GLP may not adhere to the strict record-keeping goals to which GLP aspires, undermining one of the arguments used for the value of GLP over research funding by the National Institutes of Health, which rarely follows the costly GLP guidelines. In the original publication, Tyl et al. (2008) reported that F1 retained males were necropsied at approximately 14 weeks of age. In Table 1 of her commentary (Tyl 2009), Tyl stated that these males were 18 weeks of age at necropsy. However, in testimony before the FDA Science Board BPA Subcommittee hearing on 16 September 2008 (FDALive.com 2008), Tyl stated that these males were 24 weeks of age at necropsy as an explanation for their high prostate weights. Tyl assured the FDA panel that since “the difference in age influences growth rate and growth of organs, the comparison [of 12- and 24-week-old males] is specious, it is comparing apples and oranges.” In fact, Tyl’s data in Table 1 of her commentary (Tyl 2009) show no relationship between age and body weight. The inconsistencies in Tyl’s FDA testimony, which could have had a significant impact on a regulatory decision concerning BPA, and the data concerning the age at tissue collection, prostate weights, and body weights presented in Table 1 of her commentary are disturbing, and indicate that a thorough review of original data in Tyl et al. (2008) by scientific experts is warranted.

  • Good Laboratory Practices myers et al respond
    Environmental Health Perspectives, 2009
    Co-Authors: John Peterson Myers, Frederick Vom S Saal, Julia A Taylor, Benson T Akingbemi, Koji Arizono, Scott M Belcher, Theo Colborn, Ibrahim Chahoud
    Abstract:

    We are in complete agreement with the statement by Becker et al. that “having confidence in scientific procedures and data is the sine qua non for determining the safety of chemicals and chemical products.” Our aim in writing the commentary (Myers et al. 2009) was not to challenge the original intent of Good Laboratory Practices (GLP) requirements, which was to establish standards of record keeping in contract Laboratory research so as to reduce the likelihood of fraud. Our goal instead was to show—through an analysis of the application of GLP data on bisphenol A (BPA) in regulatory proceedings—that GLP by itself is insufficient to guarantee valid and reliable science. Becker et al. appear to have missed the point of our commentary entirely. In the case of BPA, three GLP studies have been offered by industry-sponsored laboratories as proof of the chemical’s safety (Cagen et al. 1999; Tyl et al. 2002, 2008). Each has errors in study design and/or data interpretation that are sufficiently serious as to invalidate the conclusions of these studies (Myers et al. 2009). Nevertheless, because the studies were conducted using GLP guidelines, they were judged by regulators as being more reliable than the many National Institutes of Health (NIH)-funded and peer-reviewed studies that have reported adverse effects (Richter et al. 2007;vom Saal et al. 2007). As our commentary (Myers et al. 2009) clearly establishes, GLP did not guarantee the scientific validity of these three studies. Because previous analyses had identified serious flaws in the first two of those GLP studies, we focused critical attention on the most recent (Tyl et al. 2008), which both the European Food Safety Authority (EFSA 2006) and the U.S. Food and Drug Administration (FDA) had identified as key in their BPA risk assessments (FDA 2008). We found three main flaws: a) the animals were inexplicably insensitive to estrogen; b) the assays were outdated and insensitive compared with methods used in NIH-funded research showing adverse effects; and c ) validity of the findings was challenged. For example, the prostate weights of control animals reported by Tyl et al. (2008) were > 70% larger (mean, > 72 mg) than those reported by numerous laboratories, including a previously published study using CD-1 mice [conducted at RTI, where the study by Tyl et al. (2008) was conducted] that reported mean prostate weights of 46 mg in CD-1 males that were examined at a similar age (Heindel et al. 1995). Since we published our commentary (Myers et al. 2009), a possible contributor to both the estrogen insensitivity and the enlarged control prostates has been suggested: Approximately 3 years before the experiments that formed the basis of the study by Tyl et al. (2008), there was a polycarbonate fire that released BPA into the RTI Laboratory where the research was conducted (Kissinger and Rust 2009). An investigation revealed that animals in the Laboratory were exposed to low doses of BPA that government-funded science (Richter et al. 2007) indicates could affect research animals. Additional uncertainties about Tyl et al.’s study (Tyl et al. 2008) have now been identified by the lead author. Whereas the published paper reports that the animals were examined at approximately 14 weeks of age, Tyl testified at an FDA hearing in September 2008 that they were 6 months of age, and then at a German Environmental Protection Agency hearing in March 2009 that they were 5 months of age (Kissinger and Rust 2009). There she confirmed that the information in the original article was inaccurate. Because an animal’s physiology changes as it ages, these contradictory statements are problematic for all reported outcomes; even at 5–6 months of age, normal, healthy CD-1 male mice would not have the grossly enlarged prostates reported by Tyl et al. (2008). The use of flawed science, however, is not the only concern. The type of multigeneration testing approach used in these studies is, quite simply, insufficient for the testing of endocrine-disrupting chemicals. This is not a new concept. The need for more specific tests for endocrine-active compounds led in 1998 to the establishment at the U.S. Environmental Protection Agency (U.S. EPA) of the Endocrine Disruptor Screening Program, mandated by Congress (U.S. EPA 1998). After virtually no progress for over a decade, in 2009 the U.S. EPA finally announced a set of testing procedures that will be examined. The proposed “new” methodology, heavily dependent upon traditional toxicologic methods used in multigenerational GLP studies, is still woefully inadequate (Colborn 2009). The letter by Becker et al. provides a striking example of the reluctance of industry lobbyists to hear this message. In the eyes of the 36 scientific colleagues who coauthored our commentary (Myers et al. 2009), the BPA studies that Becker et al. attempt to defend are so seriously flawed as to be indefensible. Rather than continue to defend a dead issue, we encourage industry representatives to come into the 21st century and help us devise new paradigms for testing endocrine-disrupting chemicals that will safeguard human health.

  • why public health agencies cannot depend on Good Laboratory Practices as a criterion for selecting data the case of bisphenol a
    Environmental Health Perspectives, 2009
    Co-Authors: John Peterson Myers, Frederick Vom S Saal, Benson T Akingbemi, Koji Arizono, Scott M Belcher, Theo Colborn, Ibrahim Chahoud, Andrew D Crain, Francesca Farabollini, Louis J Guillette
    Abstract:

    BackgroundIn their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special pr...