Empowering Primary Care Nurse Practitioners: A Multilevel Approach to Combating the Opioid Crisis.

Aims: We offer a literature-driven, empirically informed, and highly warranted recommendation for a multilevel approach tailored to nurse practitioners. This approach aimed to drive change at the individual level (nurse practitioner), dyadic level (nurse-patient therapeutic relationship), and systems level (organisational culture, education, and policy) to strengthen nurse practitioners' capacity to deliver optimal opioid use disorder care.

Background: The opioid overdose epidemic is a global public health crisis, with the United States facing the most severe impact.

Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.

Structured approaches like the adverse outcome pathway (AOP) framework offer great potential for depicting complex toxicological processes in a manner that can facilitate informed integration of mechanistic information in regulatory decisions. While this concept provides a structure for organizing evidence and facilitates consistency in evidence integration; the process, inputs, and manner in which AOPs and AOP networks are developed is still evolving. Following the OECD guiding principles of AOP development, we propose three AOPs for male reproductive tract abnormalities and derive a putative AOP network.

Species Differences between Mouse and Human PPARα in Modulating the Hepatocarcinogenic Effects of Perinatal Exposure to a High-Affinity Human PPARα Agonist in Mice.

Evidence suggests that species differences exist between rodents and humans in their biological responses to ligand activation of PPARα. Moreover, neonatal/postnatal rodents may be more sensitive to the effects of activating PPARα. Thus, the present studies examined the effects of chronic ligand activation of PPARα initiated during early neonatal development and continued into adulthood on hepatocarcinogenesis in mice.

Diminished Hepatocarcinogenesis by a Potent, High-Affinity Human PPARα Agonist in PPARA-Humanized Mice.

Ppara-null and PPARA-humanized mice are refractory to hepatocarcinogenesis caused by the peroxisome proliferator-activated receptor-α (PPARα) agonist Wy-14,643. However, the duration of these earlier studies was limited to approximately 1 year of treatment, and the ligand used has a higher affinity for the mouse PPARα compared to the human PPARα. Thus, the present study examined the effect of long-term administration of a potent, high-affinity human PPARα agonist (GW7647) on hepatocarcinogenesis in wild-type, Ppara-null, or PPARA-humanized mice.

Facilitation of risk assessment with evidence-based methods - A framework for use of systematic mapping and systematic reviews in determining hazard, developing toxicity values, and characterizing uncertainty.

Systematic review tools and approaches developed for clinical medicine are often difficult to apply "off the shelf" in order to meet the needs of chemical risk assessments. To address such, we propose an approach that can be used by practitioners for using evidence-based methods to facilitate the risk assessment process. The framework builds on and combines efforts conducted to date by a number of agencies and researchers; the novelty is in combining these efforts with a practical understanding of risk assessment, and translating such into a 'step-by-step' guide.

Read-across: Principle, case study and its potential regulatory application in China.

Read-across, has generated much attention and has been used in many regulatory schemes as an alternative approach to testing globally. The regulatory application of read-across in the chemical management in China is progressing but still limited. A workshop on the "Read-across: Principle, case study and its potential regulatory application in China", organized by the Chemical Risk Assessment Specialty Group under the Committee of Industrial Toxicology of Chinese Society of Toxicology, was held on May 28, 2019 to discuss the potential broader application and acceptance of read-across to support chemical risk assessment in China.

Best practices for developmental toxicity assessment for classification and labeling.

Many chemicals are going through a hazard-based classification and labeling process in Europe. Because of the significant public health implications, the best science must be applied in assessing developmental toxicity data. The European Teratology Society and Health and Environmental Sciences Institute co-organized a workshop to consider best practices, including data quality and consistency, interpretation of developmental effects in the presence of maternal toxicity, human relevance of animal data, and limits of chemical classes.

Rethinking developmental toxicity testing: Evolution or revolution?

Background: Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing?

Methods: A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution).

Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action.

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities.

Quantitative weight of evidence to assess confidence in potential modes of action.

The evolved World Health Organization/International Programme on Chemical Safety mode of action (MOA) framework provides a structure for evaluating evidence in pathways of causally linked key events (KE) leading to adverse health effects. Although employed globally, variability in use of the MOA framework has led to different interpretations of the sufficiency of evidence in support of hypothesized MOAs. A proof of concept extension of the MOA framework is proposed for scoring confidence in the supporting data to improve scientific justification for MOA use in characterizing hazards and selecting dose-response extrapolation methods for specific chemicals.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (C) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and C exposures. For 13.

The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms).

The Fischer 344 (F344) rat was used by the National Toxicology Program (NTP) for over 5 decades for toxicity and carcinogenicity studies. However, in 2006, the NTP decided to switch to a different rat stock due largely to high background control incidences of Leydig cell tumors (LCTs) and mononuclear cell leukemia (MNCL), also known as large granular lymphocytic (LGL) leukemia. In the current review, we aim (1) to provide a summary of NTP bioassays with treatment-associated effects involving MNCL and LCTs in addition to male F344-specific tunica vaginalis mesothelioma (TVM); (2) to describe important pathobiological differences between these F344 rat tumor responses and similar target tissue-tumor response in humans; and (3) to present the NTP reasons for switching away from the F344 rat.

Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443).

The extended one-generation reproduction toxicity study (EOGRTS; OECD test guideline 433) is a new and technically complex design to evaluate the putative effects of chemicals on fertility and development, including effects upon the developing nervous and immune systems. In addition to offering a more comprehensive assessment of developmental toxicity, the EOGRTS offers important improvements in animal welfare through reduction and refinement in a modular study design. The challenge to the practitioner is to know how the modular aspects of the study should be triggered on the basis of prior knowledge of a particular chemical, or on earlier findings in the EOGRTS itself, requirements of specific regulatory frameworks notwithstanding.

Dissecting the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in colon, breast, and lung carcinogenesis.

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a promising drug target since its agonists increase serum high-density lipoprotein; decrease low-density lipoprotein, triglycerides, and insulin associated with metabolic syndrome; improve insulin sensitivity; and decrease high fat diet-induced obesity. PPARβ/δ agonists also promote terminal differentiation and elicit anti-inflammatory activities in many cell types. However, it remains to be determined whether PPARβ/δ agonists can be developed as therapeutics because there are reports showing either pro- or anti-carcinogenic effects of PPARβ/δ in cancer models.

Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARδ in inflammation-induced colon carcinogenesis.

The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR)-δ is highly expressed in colonic epithelial cells; however, the role of PPARδ ligands, such as fatty acids, in mucosal inflammation and malignant transformation has not been clarified. Recent evidence suggests that the anti-inflammatory/chemoprotective properties of fish oil (FO)-derived n-3 polyunsaturated fatty acids (PUFAs) may be partly mediated by PPARδ. Therefore, we assessed the role of PPARδ in modulating the effects of dietary n-3 PUFAs by targeted deletion of intestinal epithelial cell PPARδ (PPARδ(ΔIEpC)).

Functional characterization of peroxisome proliferator-activated receptor-β/δ expression in colon cancer.

This study critically examined the role of PPARβ/δ in colon cancer models. Expression of PPARβ/δ mRNA and protein was lower and expression of CYCLIN D1 protein higher in human colon adenocarcinomas compared to matched non-transformed tissue. Similar results were observed in colon tumors from Apc(+/Min-FCCC) mice compared to control tissue.

The serotonin transporter gene and startle response during nicotine deprivation.

Affective startle probe methodology was used to examine the effects of nicotine administration and deprivation on emotional processes among individuals carrying at least one s allele versus those with the l/l genotype of the 5-Hydroxytryptamine (Serotonin) Transporter Linked Polymorphic Region, 5-HTTLPR in the promoter region of the serotonin transporter gene [solute ligand carrier family 6 member A4 (SLC6A4) or SERT]. Smokers (n=84) completed four laboratory sessions crossing deprivation (12-h deprived vs. non-deprived) with nicotine spray (nicotine vs.

A natural propenoic acid derivative activates peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta).

Aims: Previous studies showed that natural prenyloxyphenylpropanoid derivatives have potent biological properties in vivo. Given the structural similarities between these compounds and known peroxisome proliferator-activated receptor (PPAR) agonists, the present study examined the hypothesis that propenoic acid derivatives activate PPARs.

Main Methods: Chimeric reporter assays were performed to identify propenoic acid derivates that could activate PPARs.

Perinatal nicotine exposure delays genital development in mice.

Introduction: Smoking has well-recognized endocrine disrupting effects in humans that have been linked specifically to nicotine in animal models. Nicotine's perinatal effects on genital development in mice, which is interpreted as a measure of endocrine disrupting activity, were evaluated in this report.

Methods: Pregnant C57B/6J dams were administered 50 microg/ml nicotine in drinking water from gestational day 9 until pups were weaned.

Activity-related behaviors in the hole-board predict nicotine consumption in C57B6 mice perinatally exposed to nicotine.

Hole-board behaviors of adolescent C57B/6 mice that had been exposed to nicotine during gestation and suckling were evaluated on postnatal days 34-36. Rearing on all three trials significantly predicted higher nicotine intake on a two-bottle choice test administered from days 37-42. For head pokes, there was a weak trend for lower head poking in the first trial to be predictive of higher nicotine intake.

Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) inhibits cell growth in a mouse mammary gland cancer cell line.

The effects of ligand activation of PPARbeta/delta were examined in the mouse mammary tumor cell line (C20). Expression of PPARbeta/delta was markedly lower in C20 cells as compared to the human non-tumorigenic mammary gland derived cell line (MCF10A) and mouse keratinocytes. Ligand activation of PPARbeta/delta in C20 cells caused upregulation of the PPARbeta/delta target gene angiopoietin-like 4 (Angptl4).