Use of Nasal Pathology in the Derivation of Inhalation Toxicity Values for Hydrogen Sulfide.

Nasal pathology can play an important role in the risk assessment process. For example, olfactory neuron loss (ONL) is one of the most sensitive end points seen in subchronic rodent hydrogen sulfide (H2S) studies and has been used by several agencies to derive health-protective toxicity values. Alternative methods that rely on computational fluid dynamics (CFD) models to account for the influence of airflow on H2S-induced ONL have been proposed. The use of CFD models result in toxicity values that are less conservative than those obtained using more traditional methods. These alternative approaches rely on anatomy-based CFD models. Model predictions of H2S delivery (flux) to the olfactory mucosal wall are highly correlated with ONL in rodents. Three major areas of focus for this review include a brief description of nasal anatomy, H2S-induced ONL in rodents, derivation of a chronic inhalation reference concentration for H2S, and the use of CFD models to derive alternative toxicity values for this gas.

Language Consideration and Methodological Transparency in "Systematic" Reviews of Animal Toxicity Studies.

This study evaluated the use of non-English literature (NEL) in systematic reviews (SRs) or meta-analyses (MAs) of animal-based toxicity or communicable disease (CD) studies. A secondary goal was to assess how grant funding, country of primary authorship, or study quality reporting influenced the use of NEL in these reviews. Inclusion criteria and data extraction forms were based on a pilot evaluation of a 10% random sample of reviews that were identified from a PubMed search (2006 to May 2017). This search yielded 111 animal toxicity and 69 CD reviews. Reviews (33 animal toxicity and 32 CD studies) were included when the authors identified their work as an SR or MA, described a literature search strategy, and provided defined inclusion criteria. Extracted data included PubMed indexing of publication type, author affiliations, and grant funding. Language use was mentioned in the methods in 55% of the toxicity SRs and 69% of CD SRs, of which 44% (n = 8) and 41% (n = 9) were limited to English, respectively. Neither the study type, grant funding, nor first author country of affiliation was associated with an increased consideration of NEL. Study quality reporting was more common in SRs that considered multiple languages. Despite guidelines that encourage the use of NEL in SRs and translation tools, SR/MA authors often fail to report language inclusion or focus on English publications. Librarian involvement in SR can promote awareness of relevant NEL and collaborative and technological strategies to improve their incorporation into the SR process.

Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence.

A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a "moderate" level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was "low" or "very low". The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.

Survey of Diplomates of the American Board of Veterinary Toxicology Regarding Perceptions of the Value of This Certification.

An anonymous, online questionnaire was sent to active diplomates of the American Board of Veterinary Toxicology (DABVTs; n = 95) to determine the attitudes of veterinary toxicologists toward their ABVT certification and the adequacy of the training programs in this discipline. We gathered information related to demographics, educational and work history, and other specialty board membership. Ten questions sought the respondent's opinion related to the economic value of the specialty, whether workforce shortages for DABVT exist, and whether DABVTs should complete a residency or graduate program. Fifty-one (54%) DABVTs responded. Their mean age was 58 and most (88%) held a graduate degree. When respondents were asked to rate their level of agreement (strongly disagree = 1; strongly agree = 5), most (73%) agreed or strongly agreed (median = 4) that there was a shortage of DABVTs. Fourteen (27%) participants strongly disagreed that the ABVT certification was required for their position, while 15 (29%) strongly agreed with this statement (median = 3). Most respondents agreed that the ABVT certification has been critical to their career (median = 4), in addition to a financial benefit to being a DABVT (median = 4). Most (67%) participants strongly or somewhat disagreed that current training programs are adequate to meet the shortage of DABVT (median = 2). Our findings indicate there is concern about the number of DABVTs and the adequacy of training programs to meet this perceived need. These findings improve our understanding of current attitudes of DABVTs toward their specialty.

Teaching Tip: Improving Students' Email Communication through an Integrated Writing Assignment in a Third-Year Toxicology Course.

Client communication is important for success in veterinary practice, with written communication being an important means for veterinarian-client information sharing. Effective communication is adapted to clients' needs and wants, and presents information in a clear, understandable manner while accounting for varying degrees of client health literacy. This teaching tip describes the use of a mock electronic mail assignment as one way to integrate writing into a required veterinary toxicology course. As part of this project, we provide baseline data relating to students' written communication that will guide further development of writing modules in other curricula. Two independent raters analyzed students' writing using a coding scheme designed to assess adherence to the guidelines for effective written health communication. Results showed that the majority of students performed satisfactorily or required some development with respect to recommended guidelines for effective written health communication to facilitate client understanding. These findings suggest that additional instruction and practice should emphasize the importance of incorporating examples, metaphors, analogies, and pictures to create texts that are comprehensible and memorable to clients. Recommendations are provided for effective integration of writing assignments into the veterinary medicine curriculum.

The effect of high dose oral manganese exposure on copper, iron and zinc levels in rats.

Manganese is an essential dietary nutrient and trace element with important roles in mammalian development, metabolism, and antioxidant defense. In healthy individuals, gastrointestinal absorption and hepatobiliary excretion are tightly regulated to maintain systemic manganese concentrations at physiologic levels. Interactions of manganese with other essential metals following high dose ingestion are incompletely understood. We previously reported that gavage manganese exposure in rats resulted in higher tissue manganese concentrations when compared with equivalent dietary or drinking water manganese exposures. In this study, we performed follow-up evaluations to determine whether oral manganese exposure perturbs iron, copper, or zinc tissue concentrations. Rats were exposed to a control diet with 10 ppm manganese or dietary, drinking water, or gavage exposure to approximately 11.1 mg manganese/kg body weight/day for 7 or 61 exposure days. While manganese exposure affected levels of all metals, particularly in the frontal cortex and liver, copper levels were most prominently affected. This result suggests an under-appreciated effect of manganese exposure on copper homeostasis which may contribute to our understanding of the pathophysiology of manganese toxicity.

Olfactory discrimination and generalization of ammonium nitrate and structurally related odorants in Labrador retrievers.

A critical aspect of canine explosive detection involves the animal's ability respond to novel, untrained odors based on prior experience with training odors. In the current study, adult Labrador retrievers (N = 15) were initially trained to discriminate between a rewarded odor (vanillin) and an unrewarded odor (ethanol) by manipulating scented objects with their nose in order to receive a food reward using a canine-adapted discrimination training apparatus. All dogs successfully learned this olfactory discrimination task (≥80 % correct in a mean of 296 trials). Next, dogs were trained on an ammonium nitrate (AN, NH4NO3) olfactory discrimination task [acquired in 60-240 trials, with a mean (±SEM) number of trials to criterion of 120.0 ± 15.6] and then tested for their ability to respond to untrained ammonium- and/or nitrate-containing chemicals as well as variants of AN compounds. Dogs did not respond to sodium nitrate or ammonium sulfate compounds at rates significantly higher than chance (58.8 ± 4.5 and 57.7 ± 3.3 % correct, respectively). Transfer performance to fertilizer-grade AN, AN mixed in Iraqi soil, and AN and flaked aluminum was significantly higher than chance (66.7 ± 3.2, 73.3 ± 4.0, 68.9 ± 4.0 % correct, respectively); however, substantial individual differences were observed. Only 53, 60, and 64 % of dogs had a correct response rate with fertilizer-grade AN, AN and Iraqi soil, and AN and flaked aluminum, respectively, that were greater than chance. Our results suggest that dogs do not readily generalize from AN to similar AN-based odorants at reliable levels desired for explosive detection dogs and that performance varies significantly within Labrador retrievers selected for an explosive detection program.

Acquisition of a visual discrimination and reversal learning task by Labrador retrievers.

Optimal cognitive ability is likely important for military working dogs (MWD) trained to detect explosives. An assessment of a dog's ability to rapidly learn discriminations might be useful in the MWD selection process. In this study, visual discrimination and reversal tasks were used to assess cognitive performance in Labrador retrievers selected for an explosives detection program using a modified version of the Toronto General Testing Apparatus (TGTA), a system developed for assessing performance in a battery of neuropsychological tests in canines. The results of the current study revealed that, as previously found with beagles tested using the TGTA, Labrador retrievers (N = 16) readily acquired both tasks and learned the discrimination task significantly faster than the reversal task. The present study confirmed that the modified TGTA system is suitable for cognitive evaluations in Labrador retriever MWDs and can be used to further explore effects of sex, phenotype, age, and other factors in relation to canine cognition and learning, and may provide an additional screening tool for MWD selection.

A Systematic Review and Meta-Analysis of the Efficacy and Safety of Rasagiline or Pramipexole in the Treatment of Early Parkinson's Disease.

Background: Rasagiline or pramipexole monotherapy has been suggested for the management of early Parkinson's disease (PD). The aim of this research was to systematically review the clinical efficacy and safety of rasagiline or pramipexole in early PD (defined as disease duration ≤5 years and Hoehn and Yahr stage of ≤3). Methods: Randomized controlled trials (RCTs) of rasagiline or pramipexole for early PD published up to September 2021 were retrieved. Outcomes of interest included changes in the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III and the incidence of adverse events. Standardized mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated, and heterogeneity was measured with the I2 test. Results: Nine rasagiline and eleven pramipexole RCTs were included. One post hoc analysis of one rasagiline study was included. Five studies for each drug were included in meta-analyses of the UPDRS scores. The rasagiline meta-analysis focused on patients receiving 1 mg/day. Rasagiline and pramipexole significantly improved UPDRS Part II and III scores when compared to placebo. Significant heterogeneity among the studies was present (I2 > 70%). Neither rasagiline nor pramipexole increased the relative risk for any adverse events, serious adverse events, or adverse events leading to withdrawal when compared with placebo. Conclusion: Applying a Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to summarize the evidence, we found moderate confidence in the body of evidence for the efficacy of rasagiline or pramipexole in early PD, suggesting further well-designed, multicenter comparative RCTs remain needed.

Updated ACVIM consensus statement on equine herpesvirus-1.

Equine herpesvirus-1 (EHV-1) is a highly prevalent and frequently pathogenic infection of equids. The most serious clinical consequences of infection are abortion and equine herpesvirus myeloencephalopathy (EHM). The previous consensus statement was published in 2009 and considered pathogenesis, strain variation, epidemiology, diagnostic testing, vaccination, outbreak prevention and control, and treatment. A recent survey of American College of Veterinary Internal Medicine large animal diplomates identified the need for a revision to this original consensus statement. This updated consensus statement is underpinned by 4 systematic reviews that addressed key questions concerning vaccination, pharmaceutical treatment, pathogenesis, and diagnostic testing. Evidence for successful vaccination against, or effective treatment of EHV-1 infection was limited, and improvements in experimental design and reporting of results are needed in future studies of this important disease. This consensus statement also updates the topics considered previously in 2009.

Pharmacologic interventions for the treatment of equine herpesvirus-1 in domesticated horses: A systematic review.

BACKGROUND: Equine herpes virus type 1 (EHV-1) infection in horses is associated with upper respiratory disease, neurological disease, abortions, and neonatal death. REVIEW QUESTION: Does pharmacological therapy decrease either the incidence or severity of disease or infection caused by EHV-1 in domesticated horses? METHODS: A systematic review was preformed searching AGRICOLA, CAB Abstracts, Cochrane, PubMed, Web of Science, and WHO Global Health Index Medicus Regional Databases to identify articles published before February 15, 2021. Selection criteria were original research reports published in peer reviewed journals, and studies investigating in vivo use of therapeutic agents for prevention or treatment of EHV-1 in horses. Outcomes assessed included measures related to clinical outcomes that reflect symptomatic EHV-1 infection or virus infection. We evaluated risk of bias and performed a GRADE evaluation of the quality of evidence for interventions. RESULTS: A total of 7009 unique studies were identified, of which 9 met the inclusion criteria. Two studies evaluated valacyclovir or small interfering RNAs, and single studies evaluated the use of a Parapoxvirus ovis-based immunomodulator, human alpha interferon, an herbal supplement, a cytosine analog, and heparin. The level of evidence ranged between randomized controlled studies and observational trials. The risk of bias was moderate to high and sample sizes were small. Most studies reported either no benefit or minimal efficacy of the intervention tested. CONCLUSIONS AND CLINICAL IMPORTANCE: Our review indicates minimal or limited benefit either as a prophylactic or post-exposure treatment for any of the studied interventions in the mitigation of EHV-1-associated disease outcome.

Inhalation dosimetry of hexamethylene diisocyanate vapor in the rat and human respiratory tracts.

Hexamethylene diisocyanate (HDI) is a reactive chemical used in the commercial production of polyurethanes. Toxic effects in rodents exposed to HDI vapor primarily occur in the nasal passages, yet some individuals exposed occupationally to concentrations exceeding current regulatory limits may experience temporary reduction in lung function and asthma-like symptoms. Knowledge of interspecies differences in respiratory tract dosimetry of inhaled HDI would improve our understanding of human health risks to this compound. HDI uptake was measured in the upper respiratory tract of anesthetized Fischer-344 rats. Nasal uptake of HDI was >90% in rats at unidirectional flow rates of 150 and 300 ml/min and a target air concentration of 200 ppb. Uptake data was used to calibrate nasal and lung dosimetry models of HDI absorption in rats and humans. Computational fluid dynamics (CFD) models of the nasal passages were used to simulate inspiratory airflow and HDI absorption. Transport of HDI through lung airways was simulated using convection-diffusion based mass transport models. HDI nasal uptake of 90% and 78% was predicted using the rat and human nasal CFD models, respectively. Total respiratory tract uptake was estimated to be 99% in rats and 97% in humans under nasal breathing. Predicted human respiratory uptake decreased to 87% under oral breathing conditions. Absorption rates of inhaled HDI in human lung airways were estimated to be higher than the rat due to lower uptake in head airways. Model predictions demonstrated significant penetration of HDI to human bronchial airways, although absorption rates were sensitive to breathing style.

Assessment of geographical variation in the respiratory toxicity of desert dust particles.

The health consequences of sand particle inhalation are incompletely understood. This project evaluated the respiratory toxicity of sand particles collected at military bases near Fort Irwin USA, in Iraq (Camp Victory, Taji and Talil), and Khost Afghanistan. Our primary focus was on assessing the role of soluble metals in the respiratory toxicity of the sand particles using in vitro and in vivo methods. Replicating rat type II alveolar cell cultures (RLE-6TN) were exposed to sand extracts or vehicle control in serum-free media for ≤24 h. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and assessment of lactate dehydrogenase leakage. The relative in vitro cytotoxicity of the sand extracts was Taji ≈ Talil > Afghanistan > Camp Victory ≈ Fort Irwin. We also assessed extracts of Camp Victory, Afghanistan, and Taji sand for acute and delayed pulmonary toxicity in rats following intratracheal administration. Assessments included biochemical analysis of bronchoalveolar lavage fluid (BALF) and lung histopathology. The in vitro cytotoxicity assay results were partially predictive of in vivo responses. The more cytotoxic Taji sand extract induced an acute irritant response in rats following intratracheal administration. Rats given the less cytotoxic Camp Victory sand extract had minimal biochemical or cytological BALF changes whereas rats given either the Afghanistan or Taji sand extracts demonstrated BALF changes that were suggestive of mild lung inflammation. Unexpectedly, we observed similar lung pathology in all extract-exposed rats. The results of our study can be used to prioritize future particle inhalation studies or guide epidemiological study design.

Subject matter expert and public evaluations of a veterinary toxicology course brochure-writing assignment.

Veterinary schools are increasingly developing students' communication skills, with an emphasis placed on practice conveying medical and scientific knowledge to different audiences. We describe how patient-centered written communication has been integrated into the training of veterinary students using toxicology-related preventive materials. Third-year veterinary students were given an assignment to prepare a client-focused brochure related to veterinary toxicology. Since 2010, 148 students have completed this assignment, with an average score of 93.4%. Use of a grading rubric was instituted in 2011 and resulted in a more rigorous assessment of the brochures by the course instructors. In this study, we evaluated a sample (n=6) selected from 10 brochures volunteered for further public and expert assessment. Each brochure was measured for readability and assessed with a rubric for perceived usefulness and acceptability by 12 veterinary toxicologists and 10 or 11 adult members of the public attending a college of veterinary medicine open house. Veterinary toxicologist review anticipated that the brochures would be useful for most clients, and the public reviewers confirmed this assessment. Evaluation of the brochures using set marking criteria and readability indexes showed that students had successfully targeted the chosen audiences. Feedback showed that the general public rated the sample brochures highly in terms of quality, usefulness, and interest. Completion of this study has resulted in revision of the grading rubric, an increased use of brochure examples, and additional instruction in readability assessment and brochure development, thereby improving the assignment as a learning exercise.

The Role of Oxidative Stress in Manganese Neurotoxicity: A Literature Review Focused on Contributions Made by Professor Michael Aschner.

This literature review focuses on the evidence implicating oxidative stress in the pathogenesis of manganese neurotoxicity. This review is not intended to be a systematic review of the relevant toxicologic literature. Instead, in keeping with the spirit of this special journal issue, this review highlights contributions made by Professor Michael Aschner's laboratory in this field of study. Over the past two decades, his laboratory has made significant contributions to our scientific understanding of cellular responses that occur both in vitro and in vivo following manganese exposure. These studies have identified molecular targets of manganese toxicity and their respective roles in mitochondrial dysfunction, inflammation, and cytotoxicity. Other studies have focused on the critical role astrocytes play in manganese neurotoxicity. Recent studies from his laboratory have used C. elegans to discover new facets of manganese-induced neurotoxicity. Collectively, his body of work has dramatically advanced the field and presents broader implications beyond metal toxicology.

Phthalates and polycystic ovary syndrome - Systematic literature review.

Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders in women, may involve both environmental and genetic factors. One potential environmental factor of concern is exposure to phthalates and other endocrine disrupting chemicals many of which have adverse effects on the female reproductive system. The aim of this systematic review was to evaluate possible association between prenatal phthalate exposure and PCOS. Six databases were searched for relevant human studies. Inclusion criteria were female human population diagnosed with PCOS and exposed during any lifestage to any phthalate or phthalate metabolite through oral, dermal, inhalation, or intravenous route. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for study quality using Joanna Briggs Institute (JBI) critical appraisal tools. The systematic literature search yielded seven articles, six case-control studies and one cohort study. Three studies found a significant positive association, two studies found a significant negative association, and two studies found no association between phthalate exposure and the incidence of PCOS. Even though studies found no consistent pattern on association with phthalates and PCOS, the results of analyzed studies did not exclude possible effects of phthalates on the female reproductive and metabolic system. Some of the factors in study design such as recruiting participants from IVF clinics and young age of participants may have biased the results. Further studies with more careful study design and longer follow-up time are needed to bring more reliable information about the role of phthalates in onset of PCOS.