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In the opening of CD II/1, Barth expounds his theological epistemology anchored in the grace of God and (thereby) the concomitant readiness of humanity for grace. In doing so he propounds a "Christian anthropology" of "blessed radical needfulness" that explicates God's creational intention for humanity, the turn of humanity to sin, and humanity's redemption in Jesus Christ. Although the significance of this positive anthropological proposal has suffered in critical discussion, a renewed look at its function discloses it to be decisive for Barth's understanding of how we as humans know God and how we understand ourselves and/or salvation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Equine herpes virus type 1 (EHV‐1) infection in horses is associated with upper respiratory disease, neurological disease, abortions, and neonatal death. Objective: To determine if there is an association between the level and duration of EHV‐1 viremia and either abortion or equine herpesvirus myeloencephalopathy (EHM) in domesticated horses? Methods: A systematic review was performed searching numerous databases to identify peer reviewed reports that evaluated viremia and EHM, or viremia and abortion published before January 19, 2021. Randomized controlled trials and observational studies were assessed for risk of bias or publication quality. Results: A total of 189 unique studies were identified, of which 34 met the inclusion criteria. Thirty studies evaluated viremia and neurologic outcomes including 4 observational studies. Eight experimental studies examined viremia and abortion, which used the Ab4 and OH03 virus strains or recombinant Ab4 derivatives. Incidence rates for both EHM and abortion in experimental studies varied among the studies as did the level of evidence. Viremia was generally detectable before the onset of either EHM or abortion. Risk of bias was generally low to moderate, sample sizes were small, and multiple studies reported negative outcome data. Conclusions and Clinical Importance: The results of this study support that viremia is regularly present before EHM or abortion occurs. However, no inferences could be made about the relationship between the occurrence of either neurological signs or abortion and the magnitude or duration of viremia. [ABSTRACT FROM AUTHOR]

Background: Equine herpesvirus type 1 (EHV‐1) infection is associated with upper respiratory disease, EHM, abortions, and neonatal death. Research Questions: Are nasal secretions a more sensitive biological sample compared to blood for the detection of EHV‐1 infection? How long is EHV‐1 detectable after primary infection by PCR? Methods: MedLine and Web of Science searches identified original peer‐reviewed reports evaluating nasal shedding and viremia using virus isolation methods or PCR published in English before October 9, 2023. Results: Sixty experimental and 20 observational studies met inclusion criteria. EHV‐1 detection frequency by qPCR in nasal secretions and blood from naturally‐infected horses with fever and respiratory signs were 15% and 9%, respectively; qPCR detection rates in nasal secretions and blood from horses with suspected EHM were 94% and 70%, respectively. In experimental studies the sensitivity of qPCR matched or exceeded that seen for virus isolation from either nasal secretions or blood. Detection of nasal shedding typically occurred within 2 days after EHV‐1 inoculation with a detection period of 3 to 7 days. Viremia lasted 2 to 7 days and was usually detected ≥1 days after positive identification of EHV‐1 in nasal secretions. Nasal shedding and viremia decreased over time and remained detectable in some horses for several weeks after inoculation. Conclusions and Clinical Importance: Under experimental conditions, blood and nasal secretions have similar sensitivity for the detection of EHV‐1 when horses are sampled on multiple consecutive days. In contrast, in observational studies detection of EHV‐1 in nasal secretions was consistently more successful. [ABSTRACT FROM AUTHOR]

Background: Equine herpes virus type 1 (EHV‐1) infection in horses is associated with respiratory and neurologic disease, abortion, and neonatal death. Hypothesis: Vaccines decrease the occurrence of clinical disease in EHV‐1‐infected horses. Methods: A systematic review was performed searching multiple databases to identify relevant studies. Selection criteria were original peer‐reviewed research reports that investigated the in vivo use of vaccines for the prevention of disease caused by EHV‐1 in domesticated horses. Main outcomes of interest included pyrexia, abortion, neurologic disease, viremia, and nasal shedding. We evaluated risk of bias, conducted exploratory meta‐analyses of incidence data for the main outcomes, and performed a GRADE evaluation of the quality of evidence for each vaccine subtype. Results: A total of 1018 unique studies were identified, of which 35 met the inclusion criteria. Experimental studies accounted for 31/35 studies, with the remainder being observational studies. Eight vaccine subclasses were identified including commercial (modified‐live, inactivated, mixed) and experimental (modified‐live, inactivated, deletion mutant, DNA, recombinant). Risk of bias was generally moderate, often because of underreporting of research methods, and sample sizes were small leading to imprecision in the estimate of the effect size. Several studies reported either no benefit or minimal vaccine efficacy for the primary outcomes of interest. Meta‐analyses revealed significant heterogeneity was present, and our confidence in the quality of evidence for most outcomes was low to moderate. Conclusions and Clinical Importance: Our review indicates that commercial and experimental vaccines minimally reduce the incidence of clinical disease associated with EHV‐1 infection. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Veterinary student education in toxicology is important. This study surveyed individuals affiliated with veterinary schools that are members of the Association of American Veterinary Medical Colleges. The online survey was designed to collect information about the credentials of the faculty that teach toxicology at veterinary schools, the topics that they include in their coursework, and faculty assessments regarding how prepared new graduates are at performing professional activities related to clinical toxicology. Nearly half of all schools provided a response to our survey. We found that toxicology was included as part of all veterinary school coursework. Toxicology classes across the different programs shared similar content. Most respondents to our survey felt that most of their students were prepared to perform professional activities related to veterinary toxicology. This study assessed the depth, breadth, and perception of toxicology education in curricula at Association of American Veterinary Medical Colleges (AAVMC) member veterinary schools. An online questionnaire was sent twice to all 54 AAVMC members and sent once to a veterinary toxicology list serve. The survey covered areas related to instructor demographics, the depth and extent of toxicology taught, and the respondent's perceptions of their student's ability to perform entrustable professional activities (EPA). Results were analyzed using descriptive statistics. Our survey resulted in a 44% response rate. All responding schools included toxicology in their curriculum, and it was a required course in 23 programs. Contact hours in stand-alone veterinary toxicology courses ranged from 14 to 45 h. Most respondents indicated that the current time allotted for toxicology was inadequate, despite indicating that most of their students could perform most EPAs autonomously. One exception related to the ability of students to analyze toxicology data. We found small variations in teaching methods and curriculum content. The results of our study can assist veterinary schools in evaluating their curricula to better prepare new graduates for the management of toxicology issues they may face in their veterinary careers. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic prompted instruction at many veterinary schools to switch to an emergency remote teaching format to prevent viral transmission associated with in-person synchronous lectures. This study surveyed student perspectives and academic performance in a preplanned online second-year veterinary toxicology course given at North Carolina State University in Spring 2020. This course relied on asynchronous narrated presentations for content delivery. This method of delivery predated the pandemic and was used throughout the course. Academic performance and patterns of access to materials in the online course was compared with the access patterns and performance of students given classroom-based synchronous teaching in Spring 2019. Assessments evaluated in this study were identical across courses. Students' academic performance was unaffected by delivery method. Lack of instructor interaction was an important perceived barrier in the asynchronous course. Asynchronous course materials were uniformly accessed across all days of the week, while supplemental materials for the face-to-face course showed a weekly pattern. Moving from letter grades to pass/fail did not change access frequency to supplemental course materials but led to decreased video usage in the asynchronous course. Results suggest that although some veterinary students perceived the switch in delivery format negatively, the method of delivery did not adversely affect performance in this preclinical course. [ABSTRACT FROM AUTHOR]

Postmortem veterinary toxicology shares challenges with human postmortem toxicology, including the necessity of analyzing a wide variety of sometimes very degraded samples for many disparate compounds. In veterinary toxicology, additional factors must be considered to formulate an appropriate testing strategy for each case. Major qualitative and quantitative species differences in response to some toxicants result in different toxicological differential lists for a given clinical presentation. The animal's environment will also influence the types of xenobiotics to which it might be exposed. Diagnostic veterinary toxicologists are veterinary medical specialists who apply their knowledge of veterinary medicine, toxicology, and analytical chemistry, to formulate and interpret results of a toxicologic testing strategy in potential poisoning cases. Animal death investigations require collaboration between veterinary diagnostic laboratory personnel (e.g., veterinary pathologists, veterinary toxicologists, and analytical chemists), veterinary practitioners, and animal owners to successfully diagnose poisoning cases. This article is categorized under:Toxicology > Post‐Mortem ToxicologyToxicology > Plants and Poisons [ABSTRACT FROM AUTHOR]

The historical reliance of state and federal funds as a sole source of veterinary educational activities has created a funding gap at many academic institutions. Due to declining resources, philanthropy has become an important source of financial support for veterinary colleges in the United States. In particular, for academic institutions with veterinary hospitals, grateful client philanthropy has been an increasingly important area of resource growth. Philanthropic gifts support innovative research, scholarship and capital, and programmatic initiatives. Areas of giving are often geared towards major infrastructure gifts and naming opportunities, faculty endowment, student scholarships, and other gift opportunities. This review provides an overview of grateful client philanthropy at North Carolina State University College of Veterinary Medicine and explores the various giving opportunities and challenges of donor giving in veterinary medicine. (129/200). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To document if a transient hypercoagulable state occurs in healthy dogs following abrupt cessation of unfractionated heparin (UFH) therapy. Design: Prospective experimental pilot study. Setting: University research facility. Animals: Seven adult random‐source male dogs. Intervention: Thromboelastography (TEG) and thrombin–antithrombin (TAT) complex formation were used to assess coagulation status in healthy dogs. Seven adult research dogs received 200–300 IU/kg subcutaneous UFH every 8 hours for 4 days. A final IV bolus of 100 IU/kg was given on day 4 and the peak measured heparin concentration 1 hour later is defined as the start of heparin withdrawal (time 0). Citrated whole blood samples were collected at baseline (prior to heparin administration) and 3, 6, 12, 30, and 48 hours after UFH withdrawal. At all time points, a kaolin‐activated TEG was performed and citrated plasma for measurement of TAT concentration was collected for batch analysis. Fibrinogen concentration, PCV, total plasma proteins, and platelet count were measured at baseline and 48 hours after heparin withdrawal. Measurements and Main Results: Compared to baseline, TAT was increased 12 hours after heparin withdrawal and returned to baseline by 30 hours. TEG clot formation time (K) was decreased 30 and 48 hours after heparin withdrawal. Conclusion: TAT results suggest that a transient increase in thrombin generation developed 12 hours after withdrawal of UFH therapy. Though clot kinetics were rapid compared to baseline beginning 30 hours after heparin withdrawal, a return to baseline was not documented. Future studies are warranted to determine the clinical relevance of these results and to evaluate the effect of UFH withdrawal in critically ill animals. [ABSTRACT FROM AUTHOR]

Superabsorbent sodium polyacrylate polymeric hydrogels that retain large amounts of liquids are used in disposable diapers, sanitary napkins, and other applications. These polymers are generally considered “nontoxic” with acute oral median lethal doses (LD50) >5 g/kg. Despite this favorable toxicity profile, we identified a novel toxic syndrome in dogs and rats following the ingestion of a commercial dog pad composed primarily of a polyacrylic acid hydrogel. Inappropriate mentation, cerebellar ataxia, vomiting, and intention tremors were observed within 24 h after the ingestion of up to 15.7 g/kg of the hydrogel by an adult, castrated male Australian Shepherd mix. These observations prompted an experimental study in rats to further characterize the toxicity of the hydrogel. Adult, female Sprague Dawley rats (n = 9) were assessed before and after hydrogel ingestion (2.6–19.2 g/kg over 4 h) using a functional observation battery and spontaneous motor activity. Clinical signs consistent with neurotoxicity emerged in rats as early as 2 h after the end of hydrogel exposure, including decreased activity in an open field, hunched posture, gait changes, reduced reaction to handling, decreased muscle tone, and abnormal surface righting. Hydrogel-exposed rats also had reduced motor activity when compared with pre-exposure baseline data. Rats that ingested the hydrogel did not develop nervous system lesions. These findings support the conclusion that some pet pad hydrogel products can induce acute neurotoxicity in animals under high-dose exposure conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The number of answer options is an important element of multiple-choice questions (MCQs). Many MCQs contain four or more options despite the limited literature suggesting that there is little to no benefit beyond three options. The purpose of this study was to evaluate item performance on 3-option versus 4-option MCQs used in a core curriculum course in veterinary toxicology at a large veterinary medical school in the United States. Methods: A quasi-experimental, crossover design was used in which students in each class were randomly assigned to take one of two versions (A or B) of two major exams. Results: Both the 3-option and 4-option MCQs resulted in similar psychometric properties. Conclusion: The findings of our study support earlier research in other medical disciplines and settings that likewise concluded there was no significant change in the psychometric properties of three option MCQs when compared to the traditional MCQs with four or more options. [ABSTRACT FROM AUTHOR]

The article argues that Karl Barth's Church Dogmatics presents human ‘neediness’ as the constitutive element of his theological anthropology. Since this element has had little notice in Barth scholarship, the article focuses on describing the consistent reiteration of this theme in theologically substantive locations throughout the Dogmatics. It begins with Barth's observation that the emergence of humanity on the sixth day discloses humans to be ‘the neediest of all creation’. Barth elaborates the dimensions of human neediness in his discussion of ‘the readiness of humanity for God’, propounding the human need for God as the precondition of knowledge of God that is in actuality undercut by the sin that denies any such neediness. Barth thus describes a potential ‘blessed neediness’ and an actual ‘wretched neediness’ that together define the glory and the tragedy of all that is human, and which inform not only Barth's epistemology and hamartiology, but also his accounts of christology, forgiveness, redemption, worship and Christian witness. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To characterize the correlation between thromboelastography (TEG) variables using strong activators and anti-Xa (AXa) activity in healthy dogs administered subcutaneous unfractionated heparin (UFH). Design Prospective experimental study. Setting University research facility. Animals Eight adult random-source male dogs. Intervention Dogs were randomized to receive subcutaneous UFH at 200, 250, or 300 IU/kg every 8 hours for a total of 10 injections. Blood samples were collected at time 0 (preheparin) and 3, 6, and 8 hours after the 1st (Day 1) and 10th (Day 4) UFH injection. After the 8-hour blood sample was obtained on day 4, a 100 IU/kg IV bolus of UFH was administered and an additional blood sample was collected 1 hour later (hour 9). AXa activity, activated partial thromboplastin time (aPTT), and TEG (with up to 5 activators) were performed at each time point. Modes of activation for TEG included recalcified (Ca), Ca with heparinase (CaH), CaH and tissue factor 1:3600 (CTF3600H), Ca with tissue factor 1:100 (CTF100), and RapidTEG. Spearman rank correlations were calculated for each of the aforementioned parameters and the AXa activity. P-values were corrected for multiple comparisons with a Bonferroni correction. Measurements and Main Results Significant correlations were found between AXa activity and the TEG R values generated with CTF100 (R = 0.83, P ≤ 0.0001) and RapidTEG (R = 0.90, P < 0.0001), as well as both forms of aPTT measurement (R = 0.86 and 0.84, P < 0.0001). Conclusions This study demonstrates that TEG variables derived using robust activation correlate with AXa activity as well as aPTT and have the potential to be used for monitoring UFH therapy in healthy dogs. Future studies are warranted to evaluate its diagnostic utility in critically ill animals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To examine available evidence on prehospital care in human and veterinary trauma and emergency medicine and develop best practice guidelines for use by both paramedical and nonparamedical personnel in the approach to the prehospital care of dogs and cats. Design Systematic evaluation of the literature gathered via medical databases searches of Medline, CAB abstracts, and Google Scholar. Synthesis From a review and systematic evaluation of the available evidence, consensus guidelines on the approach to prehospital care of dogs and cats in 18 scenarios were developed. Conclusions Due to the lack of current evidence in the veterinary prehospital arena, best practice guidelines were developed as an initial platform. Recommendations were based on a review of pertinent human and available veterinary literature as well as a consensus of the authors' professional opinions. It is anticipated that evidence-based additions will be made in the future. [ABSTRACT FROM AUTHOR]

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, NHNO) 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. [ABSTRACT FROM AUTHOR]

Concerns exist as to whether individuals may be at greater risk for neurotoxicity following increased manganese (Mn) oral intake. The goals of this study were to determine the equivalence of 3 methods of oral exposure and the rate (mg Mn/kg/ day) of exposure. Adult male rats were allocated to control diet (10 ppm), high manganese diet (200 ppm), manganesesupplemented drinking water, and manganese gavage treatment groups. Animals in the drinking water and gavage groups were given the 10ppm manganese diet and supplemented with manganese chloride (MnCl2) in drinking water or once-daily gavage to provide a daily manganese intake equivalent to that seen in the high-manganese diet group. No statistically significant difference in body weight gain or terminal body weights was seen. Rats were anesthetized following 7 and 61 exposure days, and samples of bile and blood were collected. Rats were then euthanized and striatum, olfactory bulb, frontal cortex, cerebellum, liver, spleen, and femur samples were collected for chemical analysis. Hematocrit was unaffected by manganese exposure. Liver and bile manganese concentrations were elevated in all treatment groups on day 61 (relative to controls). Increased cerebellum manganese concentrations were seen in animals from the high-manganese diet group (day 61, relative to controls). Increased (relative to all treatment groups) femur, striatum, cerebellum, frontal cortex, and olfactory bulb manganese concentrations were also seen following gavage suggesting that dose rate is an important factor in the pharmacokinetics of oral manganese. These data will be used to refine physiologically based pharmacokinetic models, extending their utility for manganese risk assessment by including multiple dietary exposures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To evaluate a point-of-care anticoagulant rodenticide lateral flow analyzer for the detection of various rodenticide compounds. Design Prospective, laboratory study. Setting University teaching hospital. Animals The study utilized a serum sample from one healthy canine donor. Samples were centrifuged and serum samples were aliquoted and either used within 4 hours or frozen at −70 °C for further quantitative analysis. Interventions Samples were spiked with clinically relevant concentrations of 1 of 6 rodenticide compounds (warfarin, pindone, chlorphacinone, brodifacoum, bromethalin, and its metabolite desmethylbromethalin). Seventy-five microliters of spiked serum (or unaltered serum) was introduced into the lateral flow test. Measurements and Main Results Three readers who were blinded to the sample preparation interpreted the lateral flow test as either positive or negative for the presence of anticoagulant rodenticide. All readers were in agreement for the results of each serum sample. The point-of-care test kit was able to detect a single anticoagulant rodenticide (warfarin) at concentrations below the manufacturer's recommended limit of detection, but was unable to detect any other anticoagulant rodenticide. Conclusions The results of this test and therapeutic interventions must be considered in light of history, physical examination, and other clinical data. Based on results from this study, the test kit only detects warfarin and not other more common second-generation anticoagulant rodenticides. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594–605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal. [ABSTRACT FROM AUTHOR]

Respiratory symptoms are frequently reported in personnel deployed to the Middle East. This project characterized the respiratory toxicity of inhaled Iraqi sand (IS). Adult rats underwent a 6-wk inhalation to air or mainstream cigarette smoke (MSCS) (3 h/d, 5 d/wk) that included exposure to IS or crystalline silica (1 mg/m3, 19 h/d, 7 d/wk) or air during the last 2 weeks. Assessments included motor activity, whole-body plethysmography, cytological and biochemical analysis of bronchoalveolar lavage fluid, lung metal burden, nasal and lung pathology, and changes in lung protein and gene expression. A number of metals including nickel, manganese, vanadium, and chromium were detected in IS. Elevated lung parenchyma aluminum, silica, barium, manganese, and vanadium concentrations were seen in IS-exposed rats, suggesting that several metals present in IS are bioavailable. Rats exposed to IS only developed mild inflammation in the anterior nose and lung. Silica inhalation was associated with some pulmonary responses that were not seen in IS-exposed rats, such as mild laryngeal and tracheal inflammation, mild tracheal epithelial hyperplasia, and elevated lung silica concentrations. MSCS inhalation with or without co-exposure to either IS or silica resulted in changes consistent with pulmonary inflammation and stress response. Rats exposed to MSCS and silica had more widespread airway lesions when compared with rats exposed to MSCS only. Silica-exposed rats had more robust pulmonary gene expression and proteomic responses than that seen in IS-exposed rat. Our studies show that the respiratory toxicity of IS is qualitatively similar to or less than that seen following short-term silica exposure. [ABSTRACT FROM AUTHOR]

Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK)models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments. [ABSTRACT FROM AUTHOR]

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers. [ABSTRACT FROM AUTHOR]

Concerns for potential vulnerability to manganese (Mn) neurotoxicity during fetal and neonatal development have been raised due to increased needs for Mn for normal growth, different sources of exposure to Mn, and pharmacokinetic differences between the young and adults. A physiologically based pharmacokinetic (PBPK) model for Mn during human gestation and lactation was developed to predict Mn in fetal and neonatal brain using a parallelogram approach based upon extrapolation across life stages in rats and cross-species extrapolation to humans. Based on the rodent modeling, key physiological processes controlling Mn kinetics during gestation and lactation were incorporated, including alterations in Mn uptake, excretion, tissue-specific distributions, and placental and lactational transfer of Mn. Parameters for Mn kinetics were estimated based on human Mn data for milk, placenta, and fetal/neonatal tissues, along with allometric scaling from the human adult model. The model was evaluated by comparison with published Mn levels in cord blood, milk, and infant blood. Maternal Mn homeostasis during pregnancy and lactation, placenta and milk Mn, and fetal/neonatal tissue Mn were simulated for normal dietary intake and with inhalation exposure to environmental Mn. Model predictions indicate similar or lower internal exposures to Mn in the brains of fetus/neonate compared with the adult at or above typical environmental air Mn concentrations. This PBPK approach can assess expected Mn tissue concentration during early life and compares contributions of different Mn sources, such as breast or cow milk, formula, food, drinking water, and inhalation, with tissue concentration. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential nutrient with the capacity for toxicity from excessive exposure. Accumulation of Mn in the striatum, globus pallidus, and other midbrain regions is associated with neurotoxicity following high-dose Mn inhalation. Physiologically based pharmacokinetic (PBPK) models for ingested and inhaled Mn in rats and nonhuman primates were previously developed. The models contained saturable Mn tissue-binding capacities, preferential fluxes of Mn in specific tissues, and homeostatic control processes such as inducible biliary excretion of Mn. In this study, a nonhuman primate model was scaled to humans and was further extended to include iv, ip, and sc exposure routes so that past studies regarding radiolabeled carrier-free 54MnCl2 tracer kinetics could be evaluated. Simulation results accurately recapitulated the biphasic elimination behavior for all exposure routes. The PBPK models also provided consistent cross-species descriptions of Mn tracer kinetics across multiple exposure routes. These results indicate that PBPK models can accurately simulate the overall kinetic behavior of Mn and predict conditions where exposures will increase free Mn in various tissues throughout the body. Simulations with the human model indicate that globus pallidus Mn concentrations are unaffected by air concentrations < 10 μg/m3 Mn. The use of this human Mn PBPK model can become a key component of future human health risk assessment of Mn, allowing the consideration of various exposure routes, natural tissue background levels, and homeostatic controls to explore exposure conditions that lead to increased target tissue levels resulting from Mn overexposure. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential element that may be toxic in conditions of overexposure. Nearly 10 years ago, some of the authors of this article published a proposed methodology to perform a tissue-dose-based risk assessment and a detailed list of data needs necessary to perform the assessment. Since that time, a substantial body of Mn pharmacokinetic (PK) data has been generated in rats and nonhuman primates, allowing for the construction of physiologically based pharmacokinetic (PBPK) models for Mn. This study reviews the development of the Mn PBPK models, reassesses the previously identified data needs, and details potential uses of these models in risk assessment of Mn. Based upon numerous animal experiments, pharmacokinetic (PK) models have effectively simulated tissue kinetics of Mn from both inhaled and oral Mn intake. PK models achieve this by incorporating homeostatic control processes, saturable tissue binding capacities, and preferential fluxes in various tissue regions. While minor data gaps still exist, the models captured the main dose-dependent characteristics of Mn disposition in rodents and monkeys and provide a structure to parameterize an equivalent PK description in humans. These models are organized to contribute to a tissue-dose based risk assessment of Mn that simultaneously considers ingestion and inhalation kinetics of Mn along with homeostatic control of Mn. [ABSTRACT FROM AUTHOR]

Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO4) in rats. Male, 16-wk-old, CD rats ( n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 μm ) containing 256 mg W/m3 as radiolabeled sodium tungstate (Na2188WO4). 188W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest 188W levels postexposure, and urinary excretion was the primary route of 188W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of 188W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings. [ABSTRACT FROM AUTHOR]

Application of Provisional Advisory Level (PAL) protocols was performed for acrylonitrile, as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL Program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. Human data were limited to inhalation exposures. The animal experimental data set for this chemical was robust for inhalation and oral studies, with the exception of appropriate data for inhalation 30-day, 90-day, and 2-year PAL 3 values. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in October 2007. Oral 24-hour PALs for acrylonitrile are PAL 1 = 7 mg/L; PAL 2 = 23 mg/L; and PAL 3 = 88 mg/L. Oral 30-day and 90-day PALs are PAL 1 = 0.35 mg/L; PAL 2 = 7 mg/L; and PAL 3 = 17 mg/L. Oral 2-year PALs are PAL 1 = 0.35 mg/L; PAL 2 = 3.5 mg/L; and PAL 3 = 12 mg/L. Acrylonitrile inhalation PAL values for 24-hour exposure are PAL 1 = 0.17 ppm; PAL 2 = 3.5 ppm; and PAL 3 = 5.1 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.15 ppm and PAL 2 = 0.60 ppm. The 2-year inhalation values are PAL 1 = 0.014 ppm and PAL 2 = 0.12 ppm. PAL 3 values for 30 days, 90 days, and 2 years are not recommended due to insufficient data. [ABSTRACT FROM AUTHOR]

Application of Provisional Advisory Levels (PALs) protocols was performed for hydrogen sulfide (H2S) as experimental data permitted. Three levels (PAL 1, PAL 2, and PAL 3), distinguished by severity of toxic effects, are developed for 24-hour, 30-day, 90-day, and 2-year durations of potential drinking water and inhalation exposures for the general public. For background on the PAL program and a description of the methodology used in deriving PALs, the reader is referred to accompanying papers in this Supplement. The database includes human experimental studies, worker exposure evaluations, as well as case studies on acute and repeated exposure. The database of animal studies is substantial, covering multiple species and addressing acute, repeated, and subchronic exposure scenarios. PAL estimates were approved by the Expert Consultation Panel for Provisional Advisory Levels in November 2006. No reliable data were found on oral exposure, making it impractical to estimate PALs for drinking water. Because H2S exists as a gas, partitioning to air is likely to occur with an environmental release. H2S inhalation PAL values for 24-hour exposure are PAL 1 = 1.2 ppm; PAL 2 = 7.0 ppm; and PAL 3 = 27 ppm; the 30-day and 90-day inhalation exposure values are PAL 1 = 0.85 ppm and PAL 2 = 3.0 ppm. PAL 3 values for 30-day and 90-day exposures are not recommended due to insufficient data. Long-term data were insufficient to estimate 2-year inhalation PALs. [ABSTRACT FROM AUTHOR]

A Physiologically Based Pharmaco Kinetic (PBPK) model, based on a published description of manganese (Mn) kinetics in adult rats, has been developed to describe Mn uptake and tissue distribution in the pregnant dam and fetus during dietary and inhalation exposures. This extension incorporated key physiological processes controlling Mn pharmacokinetics during pregnancy and fetal development. After calibration against tissue Mn concentrations observed during late gestation, the model accurately simulated Mn tissue distribution in the dam and fetus following both diet and inhalation exposures to the pregnant rat. Maternal to fetal transfer of Mn through placenta was described using two pathways: a saturable active transport with high affinity and a simple diffusion. The active transport dominates at basal and lower Mn exposure, whereas at higher Mn exposure, the relative contribution of the diffusion pathway increases. To simulate fetal tissue Mn, tissue-binding parameters and preferential influx/efflux rates in fetal brain were adjusted from the adult model based on differential developmental processes and varying tissue demands for Mn in early life. Model simulations were consistent with observed tissue Mn concentrations in fetal tissues, including brain for diet alone and for combined diet and inhalation. Simulations of Mn in placenta and other maternal tissues in late gestation correlated well with measured tissue concentrations. This model, together with our published models for Mn kinetics during lactation and postnatal development, will help to address concerns about Mn neurotoxicity in potentially sensitive human subpopulation, such as infants and children by providing an estimate of Mn exposure in the population of interest. [ABSTRACT FROM PUBLISHER]

Manganese (Mn) is an essential element. However, excess Mn causes neurotoxicity. Fetuses and neonates have been discussed as potentially sensitive subpopulations for Mn. In the present study, a previously published physiologically based pharmacokinetic model for Mn in adult rats was extended to examine exposure conditions that could lead to increased central nervous system Mn in developing rats. The basic structure had saturable tissue binding, homeostatic control of uptake and excretion, and tissue-specific increases in Mn from inhalation. Modifications made for lactating dam and pups included differential tissue-binding capacities in developing pups, increased absorption of dietary Mn in lactating dam, and more efficient gastrointestinal absorption and lower basal biliary excretion in pups. Enhancement of biliary excretion in pups was also required to accurately simulate tissue Mn during early postnatal inhalation. Overall, these changes were concordant with the biology of Mn and other essential metals during development. The resulting model simulations match a variety of published studies on maternal Mn homeostasis during lactation, milk Mn levels, and changing patterns of neonatal tissue Mn for normal dietary intake and with Mn inhalation. Our successful description of Mn kinetics across these life stages suggests that the present model can help describe the relationship between dose of exposure and target tissue Mn concentrations across different developmental stages and its potential risks and assess whether infants and children should be regarded as susceptible populations for Mn inhalation. [ABSTRACT FROM PUBLISHER]