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To investigate the differential factors associated with physician satisfaction between telemedicine and in-person visits in otolaryngology.Study data included 646 telemedicine and 365 in-person encounters delivered from May-June 2020 at a tertiary center outpatient setting. Encounter-specific physician satisfaction was rated by 15 otolaryngologists using Provider Satisfaction Questionnaire (range 0-100) consisted of 5 items (patient needs addressed, patient involvement, adequacy of information given, quality of emotion support provided, and general interaction satisfaction). A multivariable linear mixed-effects model was used to explore patient demographic and clinical factors associated with physician satisfaction.Physician satisfaction scores for telemedicine and in-person visits were 83.0 [95 % CI: 77.0-88.9] and 88.1 [95 % CI: 82.5-93.6], respectively. Among telemedicine visits, physician satisfaction scores were significantly higher for follow-up (vs. new), videoconference (vs. telephone) encounters, and English-speaking patients in a multivariable model. New encounters had significantly lower satisfaction subdomain scores for adequacy of information given to the patient (β = -4.7 [95 % CI: -7.3 to -2.0], p = 0.001) and addressing the needs of the patient among telemedicine visits (β = -4.1, [95 % CI: -7.1 to -1.1], p = 0.007) while there were no differences in satisfaction scores between new vs follow-up visits among in-person visits. For non-English speaking patients, the physician satisfaction scores were significantly lower for subdomain scores assessing active patient participation (β = -13.1, [95 % CI: -13.1 to -17.4], p 0.001) and emotional support given to the patient (β = -7.8, [95 % CI: -11.0 to -4.5], p 0.001) for telemedicine visits.Telemedicine has been broadly adopted as an alternative option to deliver care in otolaryngology since COVID-19 pandemic. Appropriate triaging based on patient and encounter characteristics may enhance physician satisfaction and overall experiences with telemedicine. Further efforts are needed to provide adequate interpretation and videoconference services during telemedicine visits.

To examine patient and physician satisfaction with telemedicine in otolaryngology during COVID-19 and identify associated factors.Prospective cohort study.Tertiary care center.Patient satisfaction was rated by patients (age ≥18 years) who had encounters from May to July 2020 (n = 407). Physician satisfaction was rated by 15 otolaryngologists for specific encounters delivered from May to June 2020 (n = 1011). Patient satisfaction was measured with a Press Ganey questionnaire and a Telemedicine Satisfaction Questionnaire. Mean Press Ganey satisfaction scores of telemedicine encounters during COVID-19 were compared with the pre-COVID-19 Press Ganey scores from in-person encounters (n = 3059) to test a noninferiority hypothesis. Physician satisfaction was measured with a Provider Satisfaction Questionnaire.The mean Press Ganey patient satisfaction score for telemedicine encounters was 94.5 (SD, 8.8), no worse than that for in-person encounters prior to COVID-19 at 93.7 (SD, 15.5; Δ = 0.8 [95% CI, -0.5 to 2.1, excluding the noninferiority margin of -1]). Encounters with videoconference (vs telephone) and patients reporting higher income were associated with higher Telemedicine Satisfaction Questionnaire scores. Physician satisfaction scores during COVID-19 with telemedicine encounters were overall high at 83.3 (95% CI, 77.5-89.1), slightly lower when compared with the scores with in-person encounters at 88.4 (95% CI, 82.5-94.3; Δ = -5.2 [95% CI, -6.6 to -3.8]). Encounters with videoconference (vs telephone) and patients with English as a preferred language and follow-up visits were associated with higher Provider Satisfaction Questionnaire scores.Telemedicine is a feasible alternative format in otolaryngology during COVID-19 with overall high patient and physician satisfaction. Patient satisfaction with telemedicine encounters during COVID-19 was no worse than in-person encounters prior to the pandemic. Physician satisfaction with telemedicine was relatively lower in comparison with in-person encounters.

Examine the rates and factors associated with under- and overreporting of subjective changes in smell or taste as compared with objective measures.Cross-sectional analysis.National Health and Nutrition Examination Survey (2013-2014).We examined participants ≥40 years old who completed subjective questionnaires (smell, n = 3510; taste, n = 3089), validated objective 8-odor pocket smell tests, and NaCl/quinine taste tests. Over- and underreporting was determined by the difference in subjective and objective results. Univariate and multivariate logistic regression analyses incorporated sampling weights.A majority of participants correctly classified impairment: smell (73.7%; 95% CI, 71.2%-76.1%) and taste (78.3%; 95% CI, 75.6%-80.7%). Age ≥65 years (odds ratio, 2.23;Although the concordance rate between subjective and objective assessment of smell and taste impairment remains high, we found that older age was associated with incorrect report of impairment. This suggests that the subjective perception of smell varies across demographical and clinical factors, and it is important to not overlook such factors in clinical practice. Potentially using a simplified odor assessment regularly in the clinical setting may aid in early detection and intervention.

Objective To estimate the prevalence of objectively confirmed olfactory and gustatory dysfunction in US adults reporting chronic rhinosinusitis (CRS) symptoms in a nationally representative database. Study Design Cross-sectional epidemiologic analysis. Setting Data were analyzed from the smell and taste component of the 2013-2014 NHANES data set (National Health and Nutrition Examination Survey). Methods Individuals reporting the presence of ≥2 cardinal CRS symptoms (nasal blockage, sinus pain, discolored mucus, and dysosmia) were identified as patients with a potential diagnosis of CRS. Associations were examined between the presence of CRS symptoms and both self-reported and objectively measured smell and taste. Results One-third (33%) of adults who have ≥2 CRS symptoms report subjective olfactory impairment, though only 18% of these adults have quantifiable olfactory dysfunction on objective testing. Of these adults, 27% report subjective taste impairment, but just 17% have quantifiable gustatory dysfunction on objective testing. The presence of ≥2 CRS symptoms was not significantly associated with objective olfactory or gustatory dysfunction, although the individual symptoms of subjective dysosmia and discolored mucus were associated with objectively confirmed olfactory dysfunction. Conclusion The prevalence of objective olfactory and gustatory dysfunction was higher among adults reporting the presence of ≥2 CRS symptoms, but the differences were not statistically significant. Specific sinonasal symptoms, including discolored mucus and subjective smell dysfunction, were significantly associated with objective smell impairment.

This article analyses Euripides’ mythopoetics in what survives of the first quarter of his fragmentaryHypsipyle:prologue, parodos, and first episode. It examines Euripides’ innovation in joining two myths (the Seven Against Thebes and the story of Hypsipyle and the Argonauts) into one, and the representation of Hypsipyle herself. In her private moments, the thoughts that preoccupy her mind are focused on other-places and other-times, in vivid contrast to the naturalistically presented world of the present where, as a slave, she must interact with men. Euripides uses the language of serving (θɛραπɛύɛιν) and doing a ‘favour’ (χάρις), as well as the word ἐρῆμος (‘lonely,’ ‘deserted’) and homoeophonic language (e.g. Argo and Argos) to indicate that, in helping the Argives, Hypsipyle repeats typologically her hospitality to the Argonauts. There is a circularity in Hypsipyle's story that creates suspense, since by doing a favour for the Argive leader, she is reunited with the sons she bore to Argonauts’ leader, who themselves are sent to find her by their grandfather whom she saved; and by losing the infant in her care (Opheltes, later named Archemorus), she is reunited with her former infants. By the end of Hypsipyle's first conversation with Amphiaraus, Euripides has invented a theme of ‘parallel worlds’ that he will resolve at the play's end.

The supraclavicular artery island (SAI) flap may be a good option for selected head and neck reconstruction due to its reliability, ease of harvest, and favorable color match. The objective of this study was to examine the rates of complications for the SAI flap in head and neck oncologic reconstruction, with examination of risk factors and comparisons to alternative flaps often considered the gold-standard soft-tissue flaps for head and neck reconstruction: the pectoralis myocutaneous (PMC), radial forearm free flap (RFFF), and anterolateral thigh (ALT) flaps.Retrospective cohort study.Consecutive SAI flaps were compared to PMC, RFFF, and ALT flaps (non-SAI flap group), all performed by the senior author from 2010 to 2018. The non-SAI flaps were included if an SAI flap could have been performed as an alternate flap. The groups were compared based on demographics, flap dimensions, site of reconstruction, operating time, total hospital stay, total hospital costs, and complications.One hundred seven SAI flaps and 194 non-SAI flaps were identified. SAI flaps were used less commonly than non-SAI flaps for mucosal defects (P .001). The SAI flap dimensions were narrower but longer than non-SAI flaps (P .001). SAI flaps had higher rates of total complications, partial flap necrosis, flap dehiscence at the recipient site, fistula, donor site dehiscence, and minor complications compared to non-SAI flaps (all P .05). SAI flaps had higher rates of total complications, recipient site dehiscence, fistula, and minor complications in both the oral cavity and all mucosal sites compared to non-SAI flaps (all P .05). SAI flaps for mucosal reconstruction were associated with higher rates of total complications (54% vs. 34%, P = .04), flap dehiscence at the recipient site (32% vs. 14%, P = .03), and major complications (21% vs. 5%, P = .02), compared to cutaneous reconstruction. Complications were equivalent between SAI flaps and non-SAI flaps for cutaneous reconstruction (all P .05). Multivariate analysis showed that SAI flaps were associated with any postoperative complication (odds ratio [OR]: 3.47, 95% confidence interval [CI]: 1.85-6.54), partial flap necrosis (OR: 5.69, 95% CI: 1.83-17.7), flap dehiscence (OR: 5.36, 95% CI: 2.29-12.5), donor site complications (OR: 11.6, 95% CI: 3.27-41.0), and minor complications (OR: 5.17, 95% CI: 2.42-11.0). Within the SAI flap group, SAI flap length 24 cm was associated with postoperative complications on multivariate analysis (OR: 5.09, 95% CI: 1.02-25.5, P = .048).The SAI flap is best suited for cutaneous reconstruction of the face, neck, and parotid/temporal bone regions due to the favorable color match; the thin, pliable nature of the skin; ease of harvest; and equivalent complication rates compared to alternate soft-tissue flaps. However, the SAI flap is associated with more complications for oral cavity and mucosal site reconstruction when compared to RFFF and ALT flaps and should be used in selected cases that do not require complex folding. For all sites, flaps longer than 24 cm should be used with caution.3 Laryngoscope, 132:S1-S14, 2022.

At the mid-point of Euripides'Hippolytus,Theseus arrives to find that his wife Phaedra has hanged herself, for a reason yet unknown. As he laments over his wife's corpse, the chorus of Troezenian women offers apparently standard consolation

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI) Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided.

A workshop addressing strategies for the genotoxicity assessment of nanomaterials (NMs) was held on October 23, 2010 in Fort Worth Texas, USA. The workshop was organized by the Environmental Mutagen Society and the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute. The workshop was attended by more than 80 participants from academia, regulatory agencies, and industry from North America, Europe and Japan. A plenary session featured summaries of the current status and issues related to the testing of NMs for genotoxic properties, as well as an update on international activities and regulatory approaches. This was followed by breakout sessions and a plenary session devoted to independent discussions of in vitro assays, in vivo assays, and the need for new assays or new approaches to develop a testing strategy for NMs. Each of the standard assays was critiqued as a resource for evaluation of NMs, and it became apparent that none was appropriate without special considerations or modifications. The need for nanospecific positive controls was questioned, as was the utility of bacterial assays. The latter was thought to increase the importance of including mammalian cell gene mutation assays into the test battery. For in-vivo testing, to inform the selection of appropriate tests or protocols, it was suggested to run repeated dose studies first to learn about disposition, potential accumulation, and possible tissue damage. It was acknowledged that mechanisms may be at play that a standard genotoxicity battery may not be able to capture.

The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper. For roughly half of these exposures, lesions appeared well before Inhibin B changed. A few of the studies showed a good correlation between seminiferous tubule damage and reduced circulating Inhibin B levels, while for seven exposures, circulating Inhibin B was reduced with no detectable alteration in testis histology. Whether this indicates a prodromal response or a false-positive signal will require further investigation. These exceptions could plausibly suggest some value of circulating Inhibin B as a useful biomarker in some circumstances. However, for roughly half of these exposures, Inhibin B appeared to be a lagging biomarker, requiring significant damage to the seminiferous tubules before a consistent and credible reduction in circulating levels of Inhibin B was observed.

BACKGROUND A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken. METHODS Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats. RESULTS Acceptable performance was defined as an overall assay coefficient of variation ≤ 20% with an intraday LLOQ ≤ 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (≤6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for ≥3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups. CONCLUSIONS The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories.

BACKGROUND: Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug-induced toxicities such as hepatic injury, which are encountered more frequently. METHODS: To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute-Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development. RESULTS: Highlights from the 16 survey respondents include: (1) Although preclinical TT was encountered relatively infrequently, half of the participants observed repeated problems with TT during pharmaceutical development, (2) despite control measures such as use of sexually mature animals to diminish confounding effects of spurious lesions, interpretation of TT remains a challenge, (3) “traditional” evaluation tools such as hormonal monitoring and newer approaches such as -omics are utilized to investigate testicular changes, and (4) an understanding of the risk and relevance of TT findings is achieved through joint consideration of factors such as species specificity, potential mode of action, and safety margins. CONCLUSIONS: TT remains a relatively uncommon but persistent challenge in pharmaceutical development. Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates. Birth Defects Res (Part B) 92: 511–525, 2011. © 2011 Wiley Periodicals, Inc.

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained.

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development. The objectives of the Workshop on The Value of Juvenile Animal Studies were to (1) provide a forum for scientists representing industry, academia, and regulatory agencies to discuss the impact of juvenile animal studies on pediatric drug development, (2) evaluate summary data from the survey to understand how the juvenile study data are being used and their impact in labeling and risk assessment, (3) discuss selected case studies from the survey to highlight key findings, and (4) identify the areas of improvement for the designs of juvenile animal studies. The take home message that resonated from the workshop discussions was that well-designed juvenile animal studies have demonstrated value in support of certain pediatric drug development programs. However, it was also clear that a juvenile animal study is not always warranted.

Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010. © 2011 Wiley-Liss, Inc.

Appropriate follow-up actions and decisions are needed when evaluating and interpreting clear positive results obtained in the in vitro assays used in the initial genotoxicity screening battery (i.e., the battery of tests generally required by regulatory authorities) to assist in overall risk-based decision making concerning the potential effects of human exposure to the agent under test. Over the past few years, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing developed a decision process flow chart to be applied in case of clear positive results in vitro. It provides for a variety of different possibilities and allows flexibility in choosing follow-up action(s), depending on the results obtained in the initial battery of assays and available information. The intent of the Review Subgroup was not to provide a prescriptive testing strategy, but rather to reinforce the concept of weighing the totality of the evidence. The Review Subgroup of the IVGT committee highlighted the importance of properly analyzing the existing data, and considering potential confounding factors (e.g., possible interactions with the test systems, presence of impurities, irrelevant metabolism), and chemical modes of action when analyzing and interpreting positive results in the in vitro genotoxicity assays and determining appropriate follow-up testing. The Review Subgroup also examined the characteristics, strengths, and limitations of each of the existing in vitro and in vivo genotoxicity assays to determine their usefulness in any follow-up testing.

The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.

Importance Problems with speech in patients with facial paralysis are frequently noted by both clinicians and the patients themselves, but limited research exists describing how facial paralysis affects verbal communication. Objective To assess the influence of facial paralysis on communicative participation. Design, Setting, and Participants A nationwide online survey of 160 adults with unilateral facial paralysis was conducted from March 1 to June 1, 2017. To assess communicative participation, respondents completed the Communicative Participation Item Bank (CPIB) Short Form questionnaire and the Facial Clinimetric Evaluation (FaCE) Scale. Main Outcomes and Measures The CPIB Short Form and the correlation between the CPIB Short Form and FaCE Scale. In the CPIB, the level of interference in communication is rated on a 4-point Likert scale (where not at all = 3, a little = 2, quite a bit = 1, and very much = 0). Total scores for the 10 items range from 0 (worst) to 30 (best). The FaCE Scale is a 15-item instrument that produces an overall score ranging from 0 (worst) to 100 (best), with higher scores representing better function and higher quality of life. Results Of the 160 respondents, 145 (90.6%) were women and 15 were men (mean [SD] age, 45.1 [12.6] years). Most respondents reported having facial paralysis for more than 3 years. Causes of facial paralysis included Bell palsy (86 [53.8%]), tumor (41 [25.6%]), and other causes (33 [20.6%]), including infection, trauma, congenital defects, and surgical complications. The mean (SD) score on the CPIB Short Form was 0.16 (0.88) logits (range, –2.58 to 2.10 logits). The mean (SD) score of the FaCE Scale was 40.92 (16.05) (range, 0-83.3). Significant correlations were observed between the CPIB Short Form and overall FaCE Scale scores, as well as the Social Function, Oral Function, Facial Comfort, and Eye Comfort subdomains of the FaCE Scale, but not with the Facial Movement subdomain. Conclusions and Relevance Patients with facial paralysis in this study sample reported restrictions in communicative participation that were comparable with restrictions experienced by patients with other known communicative disorders, such as laryngectomy and head and neck cancer. We believe that communicative participation represents a unique domain of dysfunction and can help quantify the outcome of facial paralysis and provide an additional frame of reference when assessing treatment outcomes.

The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing established an Emerging Technologies and New Strategies Workgroup to review the current State of the Art in genetic toxicology testing. The aim of the workgroup was to identify promising technologies that will improve genotoxicity testing and assessment of in vivo hazard and risk, and that have the potential to help meet the objectives of the IVGT. As part of this initiative, HESI convened a workshop in Washington, DC in May 2008 to discuss mature, maturing, and emerging technologies in genetic toxicology. This article collates the abstracts of the New and Emerging Technologies Workshop together with some additional technologies subsequently considered by the workgroup. Each abstract (available in the online version of the article) includes a section addressed specifically to the strengths, weaknesses, opportunities, and threats associated with the respective technology. Importantly, an overview of the technologies and an indication of how their use might be aligned with the objectives of IVGT are presented. In particular, consideration was given with regard to follow-up testing of positive results in the standard IVGT tests (i.e., Salmonella Ames test, chromosome aberration assay, and mouse lymphoma assay) to add weight of evidence and/or provide mechanism of action for improved genetic toxicity risk assessments in humans.

The formation of deoxyribonucleic acid (DNA) adducts can have important and adverse consequences for cellular and whole organism function. Available methods for identification of DNA damage and quantification of adducts are reviewed. Analyses can be performed on various samples including tissues, isolated cells, and intact or hydrolyzed (digested) DNA from a variety of biological samples of interest for monitoring in humans. Sensitivity and specificity are considered key factors for selecting the type of method for assessing DNA perturbation. The amount of DNA needed for analysis is dependent upon the method and ranges widely, from1 microg to 3 mg. The methods discussed include the Comet assay, the ligation-mediated polymerase reaction, histochemical and immunologic methods, radiolabeled ((14)C- and (3)H-) binding, (32)P-postlabeling, and methods dependent on gas chromatography (GC) or high-performance liquid chromatography (HPLC) with detection by electron capture, electrochemical detection, single or tandem mass spectrometry, or accelerator mass spectrometry. Sensitivity is ranked, and ranges from approximately 1 adduct in 10(4) to 10(12) nucleotides. A brief overview of oxidatively generated DNA damage is also presented. Assay limitations are discussed along with issues that may have impact on the reliability of results, such as sample collection, processing, and storage. Although certain methodologies are mature, improving technology will continue to enhance the specificity and sensitivity of adduct analysis. Because limited guidance and recommendations exist for adduct analysis, this effort supports the HESI Committee goal of developing a framework for use of DNA adduct data in risk assessment.

This workshop on the biological significance of DNA adducts included presentations of research results in the following areas: endogenous versus exogenous adduct levels; in vitro dose–response data on adducts and mutagenesis from alkylating agents; methyltransferases and alkyl transferase-like proteins in repair of O6-alkylguanine adducts; mathematical modeling of threshold dose–response in mutagenesis and carcinogenesis; and the use of genomics to characterize the relationships between adducts, gene expression, and downstream adverse effects. Presentations by regulatory scientists and other authorities addressed the role of adduct and mutation data in risk characterization. Consensus statements were developed and included the following: DNA adducts should be considered as biomarkers of exposure, which may play a key role in establishing a mode of action (MOA) for cancer. Adducts themselves should not be considered as equivalent to mutations or later stage events in carcinogenesis. Although it was not possible at this time to agree on a general level of adducts below which there is no adverse biological effect, there are examples of genotoxic mutagens/carcinogens for which thresholds have been demonstrated. Evidence regarding thresholds for mutations should be considered on a case-by-case basis, in light of available MOA and mechanistic data, to build a knowledge base. Participants agreed that guidance on a recommended format for data presentation (especially agreement on units and appropriate statistical analyses) would be beneficial. Finally, for initial cases, provision of a mechanistic explanation to support a hypothesis of a threshold for mutations was essential for the eventual use of this information in risk assessment.

c-Src non-receptor tyrosine kinase is an important component of the platelet-derived growth factor (PDGF) receptor signaling pathway. c-Src has been shown to mediate the mitogenic response to PDGF in fibroblasts. However, the exact components of PDGF receptor signaling pathway mediated by c-Src remain unclear. Here, we used stable isotope labeling with amino acids in cell culture (SILAC) coupled with mass spectrometry to identify Src-family kinase substrates involved in PDGF signaling. Using SILAC, we were able to detect changes in tyrosine phosphorylation patterns of 43 potential c-Src kinase substrates in PDGF receptor signaling. This included 23 known c-Src kinase substrates, of which 16 proteins have known roles in PDGF signaling while the remaining 7 proteins have not previously been implicated in PDGF receptor signaling. Importantly, our analysis also led to identification of 20 novel Src-family kinase substrates, of which 5 proteins were previously reported as PDGF receptor signaling pathway intermediates while the remaining 15 proteins represent novel signaling intermediates in PDGF receptor signaling. In validation experiments, we demonstrated that PDGF indeed induced the phosphorylation of a subset of candidate Src-family kinase substrates – Calpain 2, Eps15 and Trim28 – in a c-Src-dependent fashion.

Efficient management of chronic sinusitis remains a great challenge for primary care physicians. Unlike ENT specialists using Computed Tomography scans, they lack an affordable and safe method to accurately screen and monitor sinus diseases in primary care settings. Lack of evidence-based sinusitis management leads to frequent under-treatments and unnecessary over-treatments (i.e. antibiotics). Previously, we reported low-cost optical imaging designs for oral illumination and facial optical imaging setup. It exploits the sensitivity of NIR transmission intensity and their unique patterns to the sinus structures and presence of fluid/mucous-buildup within the sinus cavities. Using the improved NIR system, we have obtained NIR sinus images of 45 subjects with varying degrees of sinusitis symptoms. We made diagnoses of these patients based on two types of evidence: symptoms alone or NIR images along. These diagnostic results were then compared to the gold standard diagnosis using computed tomography through sensitivity and specificity analysis. Our results indicate that diagnosis of mere presence of sinusitis that is, distinguishing between healthy individuals vs. diseased individuals did not improve much when using NIR imaging compared to the diagnosis based on symptoms alone (69% in sensitivity, 75% specificity). However, use of NIR imaging improved the differential diagnosis between mild and severe diseases significantly as the sensitivity improved from 75% for using diagnosis based on symptoms alone up to 95% for using diagnosis based on NIR images. Reported results demonstrate great promise for using NIR imaging system for management of chronic sinusitis patients in primary care settings without resorting to CT.

The 1998 U.S. Environmental Protection Agency Office of Pesticide Programs (OPP) re-registration eligibility decision (RED) for phosphine fumigants has generated much interest in defining safe levels of exposure for workers and worker bystanders. This report summarizes the pertinent literature on phosphine toxicity, including animal inhalation studies and human epidemiology studies, and also describes a margin-of-exposure (MOE) analysis based on available worker exposure data. In addition, a safe occupational exposure limit is estimated using typical OPP assumptions, after determination of appropriate uncertainty factors, based on quality of data in the principal study and pharmacokinetic considerations. While a conservative 8-hour time-weighted average (TWA) of 0.1 ppm was calculated, the overall weight of evidence, from a risk-management perspective, supports a conclusion that an occupational TWA of 0.3 ppm provides adequate health protection. In addition, a 15-minute short-term exposure limit (STEL) of 3 ppm was estimated. Finally, in contrast to the MOE analysis described in the OPP's phosphine RED, the MOE analysis described herein does not indicate that fumigation workers are currently being exposed to unacceptable levels of phosphine. Collectively, these findings support the occupational exposure limits of 0.3 ppm (8-hour TWA) and 1 ppm (STEL) established in the updated applicator's manuals for phosphine-generating products, which recently received approval from OPP.

The existence of a compound from the tubular fraction of the testis which acts on the pituitary was first proposed in writing by McCullagh in 1932. This was inferred by observing the differential effects on the prostate and the pituitary when animals were administered water-soluble or ether-soluble extracts of testis. Because the water-soluble extract inhibited pituitary hypertrophy, he dubbed this moiety inhibin (his androitin for the ether-soluble actor later became testosterone). The early literature has been nicely reviewed (Ying, 1988). The early assays for inhibin were bioassays (e.g., Steinberger and Steinberger, 1976), later superseded by the more-sensitive radioimmunoassays, and now ELISAs. Inhibin has been used for several years as a clinical tool to help diagnose and categorize male infertility patients (e.g., Pierik et al., 1998; reviewed in Lockwood 2004, Adamopoulos and Koukkou, 2010, and Anderson and Sharpe, 2000). There has been a robust literature on various aspects on the physiology of the hormone, for example, trying to discern what controls circulating levels of Inhibin B in males (e.g., Ramaswamy et al., 1999), or describing the relationship between Inhibin and FSH (e.g., von Eckerdstein et al., 1999; Kamischke et al., 2001), or determining the impact of different germ cell populations on circulating Inhibin B levels (e.g., Pineau et al., 1989; Allenby et al., 1991; Clifton et al., 2002), or outlining Inhibin B’s role in development (Byrd et al., 1998) or evaluating its use as an epidemiologic marker (e.g., Ellingsen et al., 2007). There are numerous excellent reviews on this subject, a few of which are Meachem et al. (2001), de Kretser et al. (2004), and Stewart and Turner (2005). Because the large interand intraindividual variability makes sperm count and semen studies quite insensitive (e.g., Schrader et al., 1988), toxicologists and epidemiologists have long been looking for a more sensitive (i.e., less noisy and more responsive) biomarker of damage to the seminiferous tubules. Inhibin B seemed to fill this need, and indeed was found to respond to several different types of toxicities, especially over sufficient periods of time (Wallace et al., 1997; Tsatsoulis et al., 1988; Foppiani et al., 1999; Hild et al., 2001; Suescun et al., 2001; rev. in Stewart and Turner, 2005; Tunc et al., 2006).

Since regulatory agencies began implementing the use of standardized developmental toxicology protocols in the mid-1960s, our knowledge base of embryo-fetal development and technologies for experimentation has grown exponentially. These developmental toxicology protocols were a direct result of the thalidomide tragedy from earlier that decade, when large numbers of women were exposed to the drug and over 10,000 cases of phocomelia resulted. In preventing a recurrence of such tragedies, the testing protocols are immensely successful and the field of toxicology has been dedicated to using them to advance safety and risk assessment of chemicals and pharmaceuticals. Recently, our perspectives on toxicity testing have been challenged by a growing awareness that while we have excelled in hazard identification, we are in dire need of improved methodologies for human health risk assessment, particularly with respect to the large numbers of environmental chemicals for which we have little toxicology data and to the growing sentiment that better alternatives to whole animals tests are needed. To provide a forum for scientists, researchers, and regulators, the Developmental and Reproductive Toxicology Technical Committee of the Health and Environmental Sciences Institute organized a 2-day workshop titled "Developmental Toxicology-New Directions" to evaluate lessons learned over the past 30 years and discuss the future of toxicology testing. The following four articles describe different presentations and discussions that were held over the course of those 2 days.

To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing. This workshop report is intended to provide scientists with a broad overview of relevant testicular toxicity literature and to suggest opportunities where bioengineering principles and techniques could be used to build improved in vitro testicular models for safety evaluation. Tissue engineering techniques could, conceivably, be immediately implemented to improve existing models. However, it is likely that in vitro testis models that use single or multiple cell types will be needed to address such endpoints as accurate prediction of chemically induced testicular toxicity in humans, elucidation of mechanisms of toxicity, and identification of possible biomarkers of testicular toxicity. published

Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous "yes" or "no" manner without analysis of dose-response relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose-response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose-response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effect-level (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL(10) ) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose-response data.

A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken.Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats.Acceptable performance was defined as an overall assay coefficient of variation ≤ 20% with an intraday LLOQ ≤ 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (≤6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for ≥3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups.The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories.

The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper. For roughly half of these exposures, lesions appeared well before Inhibin B changed. A few of the studies showed a good correlation between seminiferous tubule damage and reduced circulating Inhibin B levels, while for seven exposures, circulating Inhibin B was reduced with no detectable alteration in testis histology. Whether this indicates a prodromal response or a false-positive signal will require further investigation. These exceptions could plausibly suggest some value of circulating Inhibin B as a useful biomarker in some circumstances. However, for roughly half of these exposures, Inhibin B appeared to be a lagging biomarker, requiring significant damage to the seminiferous tubules before a consistent and credible reduction in circulating levels of Inhibin B was observed.

The current political and societal climate is driving the science of toxicology towards developing non-animal testing methodologies. Though alternative and in vitro tests have always been a mainstay for toxicological testing, technological advances in the last decade have allowed toxicologists to move rapidly towards a better understanding of the relevance of in vitro endpoints for traditional apical endpoints. Non-animal research using new technologies have illuminated toxicologists on the mechanisms of protection and adverse health outcomes. In this context, the "validation" of alternative and in vitro tests has taken on significant importance, particularly in regard to satisfying safety concerns of drugs and chemicals in a regulatory setting. The purpose of this chapter is to briefly review the impetus for the development of alternative and in vitro tests, discuss the projects underway at the ILSI Health and Environmental Sciences Institute (HESI) that are oriented towards this topic, and summarize the processes for formal validation. It should be noted that though there are validated assays and tests, these are under constant evaluation by scientific researchers as our understanding of the underlying biological processes continues to evolve.

The current political and societal climate is driving the science of toxicology towards developing non-animal testing methodologies. Though alternative and in vitro tests have always been a mainstay for toxicological testing, technological advances in the last decade have allowed toxicologists to move rapidly towards a better understanding of the relevance of in vitro endpoints for traditional apical endpoints. Non-animal research using new technologies have illuminated toxicologists on the mechanisms of protection and adverse health outcomes. In this context, the "validation" of alternative and in vitro tests has taken on significant importance, particularly in regard to satisfying safety concerns of drugs and chemicals in a regulatory setting. The purpose of this chapter is to briefly review the impetus for the development of alternative and in vitro tests, discuss the projects underway at the ILSI Health and Environmental Sciences Institute (HESI) that are oriented towards this topic, and summarize the processes for formal validation. It should be noted that though there are validated assays and tests, these are under constant evaluation by scientific researchers as our understanding of the underlying biological processes continues to evolve.

A workshop addressing strategies for the genotoxicity assessment of nanomaterials (NMs) was held on October 23, 2010 in Fort Worth Texas, USA. The workshop was organized by the Environmental Mutagen Society and the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute. The workshop was attended by more than 80 participants from academia, regulatory agencies, and industry from North America, Europe and Japan. A plenary session featured summaries of the current status and issues related to the testing of NMs for genotoxic properties, as well as an update on international activities and regulatory approaches. This was followed by breakout sessions and a plenary session devoted to independent discussions of in vitro assays, in vivo assays, and the need for new assays or new approaches to develop a testing strategy for NMs. Each of the standard assays was critiqued as a resource for evaluation of NMs, and it became apparent that none was appropriate without special considerations or modifications. The need for nanospecific positive controls was questioned, as was the utility of bacterial assays. The latter was thought to increase the importance of including mammalian cell gene mutation assays into the test battery. For in-vivo testing, to inform the selection of appropriate tests or protocols, it was suggested to run repeated dose studies first to learn about disposition, potential accumulation, and possible tissue damage. It was acknowledged that mechanisms may be at play that a standard genotoxicity battery may not be able to capture.

In April 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute’s (HESI) Developmental and Reproductive Toxicology Technical Committee held a two-day workshop entitled “Developmental Toxicology—New Directions.” The third session of the workshop focused on ways to refine animal studies to improve relevance and predictivity for human risk. The session included five presentations on: (1) considerations for refining developmental toxicology testing and data interpretation; (2) comparative embryology and considerations in study design and interpretation; (3) pharmacokinetic considerations in study design; (4) utility of genetically modified models for understanding mode-of-action; and (5) special considerations in reproductive testing for biologics. The presentations were followed by discussion by the presenters and attendees. Much of the discussion focused on aspects of refining current animal testing strategies, including use of toxicokinetic data, dose selection, tiered/triggered testing strategies, species selection, and use of alternative animal models. Another major area of discussion was use of non-animal-based testing paradigms, including how to define a “signal” or adverse effect, translating in vitro exposures to whole animal and human exposures, validation strategies, the need to bridge the existing gap between classical toxicology testing and risk assessment, and development of new technologies. Although there was general agreement among participants that the current testing strategy is effective, there was also consensus that traditional methods are resource-intensive and improved effectiveness of developmental toxicity testing to assess risks to human health is possible. This article provides a summary of the session’s presentations and discussion and describes some key areas that warrant further consideration.

The Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), initiated a project committee entitled “Relevance and Follow-up of Positive Results from In Vitro Genetic Toxicity Testing (IVGT)” with the overall objective of improving the scientific basis for the interpretation of results from genetic toxicology testing. The IVGT committee has also recognized the need to develop follow-up strategies for determining the relevance of in vitro test results to human health, and moving genetic toxicology testing from the sole purpose of hazard identification toward a more quantitative risk assessment approach. In this context, a group of experts evaluated the potential utility of the emerging in vivo mutational assessment model commonly known as the Pig-a gene mutation assay to follow-up positive in vitro genetic toxicology findings and to generate robust dose-response data for quantitative assessment of the in vivo mutagenicity. The IVGT experts participating in this effort represented academia, industry, and government agencies from across the globe and addressed such issues as the optimal sample size and experimental design for generating robust dose-response data. This expert group concluded that the emerging Pig-a gene mutation assay holds great promise as an in vivo mutagenicity assay, either as a stand-alone study or integrated into repeat-dose toxicology studies, and therefore supports further validation of the model. Environ. Mol. Mutagen. 2011. © 2011 Wiley-Liss, Inc.

The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled “Developmental Toxicology—New Directions” in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program. Issues discussed include the challenges of anchoring in vitro predictions to relevant in vivo endpoints and the need to validate pathway-based predictions with targeted studies in whole animals. Currently, there are 10,000 to 30,000 chemicals in world-wide commerce in need of hazard data for assessing potential health risks. The traditional animal study designs for assessing developmental toxicity cannot accommodate the evaluation of this large number of chemicals, requiring that alternative technologies be utilized. Though a daunting task, technologies are being developed and utilized to make that goal reachable. Birth Defects Res (Part B) 92:413–420, 2011. © 2011 Wiley Periodicals, Inc.

This review is the second in a series of four papers emanating from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the ILSI Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. The present review analyzes the strengths and weaknesses of current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e.g., large number of animals, high costs, low throughput, the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models relative to mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century.