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In aesthetic practice, wrinkles in the upper face are commonly treated with repeat-dose injections. The objective of this study was to investigate the safety, tolerability, and efficacy of repeat-dose injections of incobotulinumtoxinA in the combined treatment of moder-ate to severe upper facial lines (UFL) [glabellar frown lines (GFL), horizontal forehead lines (HFL), and lateral periorbital lines (LPL)]. Healthy subjects (ge;18 years) with moderate to severe GFL, HFL, and LPL on the Merz Aesthetics Scales (MAS) at maximum contrac-tion were administered 54 to 64 U of incobotulinumtoxinA (GFL, 20 U; HFL, 10 to 20 U; LPL, 24 U) in up to four, 120-day treatment cycles. Adverse events (AE) were recorded for each cycle until 120plusmn; 7 days after treatment. Investigator-assessed MAS scores were evaluated for each treated area at maximum contraction on day 30 [responder = score ofldquo;nonerdquo; (0) orldquo;mildrdquo; (1)]. Subject-assessed scores for overall appearance of the upper face ofldquo;much improvedrdquo; orldquo;very much improvedrdquo; were noted at day 30 of each treatment cycle on the Global Impression of Change Scale (GICS). Overall, 140 subjects were treated, and 125 subjects completed the study. Mean injected units per injection cycle ranged from 56.3 U to 57.7 U. During the four-cycle study period 17.1% of total treated subjects experienced a treatment emergent adverse event (TEAE). TEAEs of special interest were documented for 9 subjects (6.4%), in 6 of these subjects (4.3%) the TEAEs were related to treatment. No clinically significant mean changes in laboratory and vital-sign values were observed from screening to final-treatment visit. Over the study interval, a response rate ofgt; 80% on the investigator-assessed MAS was reported for all treated areas except HFL. Greater than 80% of subjects in cycles 1, 3, and 4 and 78.5% of subjects in cycle 2 reported ratings ofldquo;much improvedrdquo; orldquo;very much improvedrdquo; on the GICS for the overall appearance of the upper face. Incobotu-linumtoxinA for the repeat-dose treatment of UFL is safe and well tolerated with a stable safety profile, without new formation of neutralizing antibodies and has excellent efficacy during prolonged administration. J Drugs Dermatol. 2020;19(5):461-469. doi:10.36849/JDD.2020.5013.

Tranexamic acid (TXA) is a well-tolerated hemostatic agent that has been in clinical use for nearly 60 years. In this report, we describe for the first time 10 patients who experienced adverse reactions to repeat dose of TXA, which were not seen with the first dose. Shivering was found to be the most common adverse reaction. In half of the cases, shivering was associated with low-grade fever. On dechallenge and subsequent administration of steroids and antihistaminic agents, the reactions were controlled. On assessment with the World Health Organization–Uppsala Monitoring Centre scale, the causality was ascertained to be “Probable”.There is no clear postulated mechanism for shivering with TXA. We have postulated that hypersensitivity, fever, and shivering in these patients may be interlinked. In the light of this report, the physicians should take into account that repeated challenge with TXA may lead to adverse reactions in some patients and withdrawing the drug in such patients may be required.

Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a new class of factor VIII (FVIII) replacement that breaks the von Willebrand factor–imposed FVIII half-life ceiling. In a phase 1/2a study, single-dose efanesoctocog alfa was well tolerated, and no safety concerns were identified. We evaluated the safety, tolerability, and pharmacokinetics of repeat-dose efanesoctocog alfa in a phase 1 study in previously treated adults (≥150 exposure days) with severe hemophilia A. Participants received 4 once weekly doses of efanesoctocog alfa (cohort 1, 50 IU/kg; cohort 2, 65 IU/kg). All enrolled participants (cohort 1, n = 10; cohort 2, n = 14) completed the study. Inhibitor development to FVIII was not detected. After the last dose of efanesoctocog alfa, geometric mean (range) FVIII activity half-life, area under the activity-time curve, and steady-state maximum concentration for cohort 1 and cohort 2 were 41.3 (34.2-50.1) and 37.3 (28.9-43.8) hours, 8290 (5810-10 300) and 11 200 (7040-15 800) hours × IU/dL, and 131 (96-191) and 171 (118-211) IU/dL, respectively. There was minimal accumulation after 4 doses. Mean FVIII activity for cohort 1 and cohort 2, respectively, was 46% and 69% on day 3 postdose and 10% and 12% on day 7 postdose. Overall, 4 once-weekly doses of efanesoctocog alfa were well tolerated, no safety concerns were identified, and no bleeds were reported during the treatment period. Once-weekly efanesoctocog alfa provided high sustained FVIII activity within the normal to near-normal range for 3 to 4 days postdose and may improve protection against bleeds in patients with hemophilia A. The trial is study 2018-001535-51 in the EU Clinical Trials Register.

In the context of REACH and the EU ban on animal testing of cosmetic ingredients, development, adoption and acceptance of non-animal methods is urgent. Read-across is the predominate non-animal method being used for higher tier endpoints (repeat dose and developmental and reproductive toxicity). The limitations of read-across include the lack of suitable analogs and analog data for all chemicals of interest, as well as concerns with missing a potential adverse response that results from small differences in chemical structure. In this manuscript we explore two possible enhancements to read-across approaches in the context of a single case study: read-across assessments based on metabolite data and incorporation of in vitro data to support the read-across hypothesis. We use this case study to explore possible paths forward in implementing these enhancements, but more importantly to raise issues that need to be resolved prior to extensive use and hopefully acceptance of these expanded approaches. For the case of read-across based on metabolites, we explore the potential application of an internal dose TTC (iTTC) approach to address uncertainty associated with potential toxicity from exposure to residual parent chemical. This is a relevant scenario for the many cosmetic ingredients containing ester structures. For the use of in vitro data we explore considerations that must be taken before the application of ToxCast™ data to the read-across to ensure positive responses are reliable and relevant. As more cosmetic ingredients are tested in in vitro systems, guidance on the appropriate interpretation of these data will be essential. The concept of dosimetry is a unifying need that must be addressed in both these approaches. In the present paper, we explore how to use and apply internal dose metrics to address some issues associated with expanded approaches in read-across.

If nonhuman primates represent the only relevant species for nonclinical safety evaluation of biotechnology-derived products, male and female fertility effects can be assessed in repeat dose toxicity studies given that sexually mature monkeys are used. This opinion piece provides recommendations for determining sexual maturity and when/how fertility assessments should be conducted in the cynomolgus monkey. Male sexual maturity should be proven by presence of sperm in a semen sample, female sexual maturity by at least two consecutive menstrual bleedings. As per regulatory guidance, default parameters for an indirect assessment of fertility in both sexes are reproductive organ weight and histopathology. Beyond default parameters, daily vaginal swabs are recommended for females, and for males, it is recommended to include blood collections (for potential analysis of reproductive hormones), testis volume sonography, and collection of frozen testis samples at necropsy. Only if there is a cause for concern, blood collection for potential reproductive hormone analysis should be conducted in females and semen analysis in males. In principle, adverse reproductive effects can be detected within 4 weeks of test article administration, depending on study design and reproductive end point chosen. Therefore, there are options for addressing reproductive toxicity aspects with studies of less than 3 months dosing duration. *This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Cigarette smoking is a risk factor for several lung diseases, including chronic obstructive pulmonary disease, cardiovascular disease, and lung cancer. The potential health effects of chronic use of electronic nicotine delivery systems (ENDS) is unclear. This study utilized fully differentiated primary normal human bronchial epithelial (NHBE) cultures in a repeat-dose exposure to evaluate and compare the effect of combustible cigarette and ENDS preparations. We show that 1-h daily exposure of NHBE cultures over a 10-day period to combustible cigarette whole smoke-conditioned media (WS-CM) increased expression of oxidative stress markers, cell proliferation, airway remodeling, and cellular transformation markers and decreased mucociliary function including ion channel function and airway surface liquid. Conversely, aerosol conditioned media (ACM) from ENDS with similar nicotine concentration (equivalent-nicotine units) as WS-CM and nicotine alone had no effect on those parameters. In conclusion, primary NHBE cultures in a repeat-dose exposure system represent a good model to assess the features of lung disease. This study also reveals that cigarette and ENDS preparations differentially elicit several key endpoints, some of which are potential biomarkers for lung cancer or chronic obstructive pulmonary disease (COPD).

To protect human health, acute reference values have been established for pesticides which have the potential to cause a toxic effect after acute human exposure. These values are used to identify exposure levels below which there is no appreciable risk. Comprehensive reference documents, including OECD criteria, are available to aid identification of relevant toxicological endpoints. Within Europe, there is a concern that the identification process is inconsistent and unnecessarily conservative such that safe products with no established human health risk are being restricted. For this reason, the basis for the setting of an acute reference dose (ARfD) has been investigated for 130 pesticides to better understand how the toxicological endpoints are selected. The investigation has shown that most ARfDs are derived from repeat dose studies and that there is an over-representation of prenatal developmental toxicity studies. There is clear evidence that ARfDs derived from rabbit developmental toxicity studies are set over conservatively with regard to acute maternal effects and often inappropriately. To facilitate an improved system, refinements to the existing process are recommended, the use of maternal data in the rabbit as the basis for deriving an ARfD is critically evaluated and a new, more pragmatic approach to ARfD derivation is proposed.

PGBH is an uncommon individual risk but nevertheless cumulatively prevalent and important consequence of gastric bypass for the management of obesity. It is characterized by dysregulated hyperinsulinism (HI) and significant postprandial hypoglycemia and is not adequately treated with existing therapies. RZ358 is a human monoclonal antibody which allosterically attenuates the binding and action of insulin at target cell insulin receptors (IR), only during high insulin states. In previous clinical studies in induced (healthy volunteer insulin tolerance test) and intrinsic (congenital) hyperinsulinism, RZ358 showed favorable safety and PK, and glucose normalization without hyperglycemia. Therefore, RZ358 may also be beneficial in treating PGBH. The present study is a Phase 2a, single ascending (3, 6, and 9 mg/kg) and repeat dose (3 mg/kg/week for 4 weeks) study of IV RZ358 in patients with PGBH (n=16 [M:2; F:14]). Serial measurements of plasma RZ358 and biomarkers, and continuous glucose monitoring (CGM) were performed for up to 6 weeks. PK/PD modeling was conducted using NONMEM (v7.3) to describe RZ358 concentrations and exposure response (ER) relationships. Other than gender, baseline characteristics were similar between cohorts. RZ358 was safe and well-tolerated overall, with no discontinuations, deaths, or serious adverse reactions. The observed concentrations were well-described by the developed PK model, with dose-proportional exposures, an estimated effective half-life of ~15 days, and PK that was comparable to that in healthy volunteers and congenital HI. Concentration-dependent increases in insulin of up to 4-fold were observed, due to reduced IR clearance, as supported by unchanged c-peptide levels. Concentration-dependent increases in ketones and free fatty acids were also observed, providing further biomarker evidence of insulin attenuation by RZ358 at target tissues. RZ358 resulted in an apparent saturable ER with a ceiling response at normoglycemic values, showing sustained glucose increases by CGM over several weeks after dosing. Patients with the most pronounced postprandial hypoglycemia at baseline experienced an average ~60% glucose increase (by min/day

In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was developed. Systemic effect levels were curated from ToxRefDB, HESS-DB and COSMOS-DB from numerous study types totaling 4379 in vivo studies for 1247 chemicals. Observed systemic effects in mammalian models are a complex function of chemical dynamics, kinetics, and inter- and intra-individual variability. To address this complex problem, systemic effect levels were modeled at the study-level by leveraging study covariates (e.g., study type, strain, administration route) in addition to multiple descriptor sets, including chemical (ToxPrint, PaDEL, and Physchem), biological (ToxCast), and kinetic descriptors. Using random forest modeling with cross-validation and external validation procedures, study-level covariates alone accounted for approximately 15% of the variance reducing the root mean squared error (RMSE) from 0.96 log10 to 0.85 log10 mg/kg/day, providing a baseline performance metric (lower expectation of model performance). A consensus model developed using a combination of study-level covariates, chemical, biological, and kinetic descriptors explained a total of 43% of the variance with an RMSE of 0.69 log10 mg/kg/day. A benchmark model (upper expectation of model performance) was also developed with an RMSE of 0.5 log10 mg/kg/day by incorporating study-level covariates and the mean effect level per chemical. To achieve a representative chemical-level prediction, the minimum study-level predicted and observed effect level per chemical were compared reducing the RMSE from 1.0 to 0.73 log10 mg/kg/day, equivalent to 87% of predictions falling within an order-of-magnitude of the observed value. Although biological descriptors did not improve model performance, the final model was enriched for biological descriptors that indicated xenobiotic metabolism gene expression, oxidative stress, and cytotoxicity, demonstrating the importance of accounting for kinetics and non-specific bioactivity in predicting systemic effect levels. Herein, we generated an externally predictive model of systemic effect levels for use as a safety assessment tool and have generated forward predictions for over 30,000 chemicals. Electronic supplementary material The online version of this article (doi:10.1007/s00204-017-2067-x) contains supplementary material, which is available to authorized users.

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily., This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0–τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0–14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.)

Introduction The pentylenetetrazole (PTZ)-induced seizure assay in rodents is an established method for investigating drug-induced alterations in seizure threshold such as proconvulsant effects. The standard procedure in our laboratory was to administer the test item prior to 75–120 mg/kg subcutaneous PTZ. However, this dose range is associated with a high incidence of mortality, including approximately 40% or greater deaths of control animals. Methods The predictivity of the PTZ-induced seizure assay was retrospectively evaluated by relating drug plasma levels associated with proconvulsant effects to exposures observed during convulsions in repeat-dose toxicology studies. Margins to estimated efficacious doses were also considered. To investigate potential refinements, a high PTZ dose (80 mg/kg, subcutaneously) was compared to two lower doses (40 and 60 mg/kg), and a range of doses of theophylline was orally administered as positive control. Results The PTZ-induced proconvulsion assay proved to be a good predictor of convulsions in toxicology studies. In the refinement study, theophylline potentiated PTZ–induced seizures over all doses tested. At 60 mg/kg PTZ, the proconvulsant dose-dependency of theophylline was best observed. At both 40 and 60 mg/kg PTZ, mortality in control animals was significantly reduced. Discussion Risk assessment at an early stage of drug development supports candidate selection and, along that approach, the PTZ proconvulsion assay was proven to be a good predictor of convulsions in subsequent toxicology studies. It was also demonstrated that a relatively lower PTZ dose (60 mg/kg) improved the dose-response-curve of the positive control tested, decreased mortality overall and, therefore, contributes to refining this standard procedure for CNS safety evaluation.

Recently introduced Mindray "3-directional" neuromuscular transmission transducer (NMT, Shenzhen, China) acceleromyograph) claim to monitor thumb movement in 3 different directions. We compared NMT with the gold standard Relaxometer® mechanomyograph (MMG, Groningen University, Netherlands) in Study-1 and with TOF-Watch SX™ (WTCH) acceleromyograph from which it was developed in Study-2. We used first twitch (T1%) and train-of-four (TOF) ratio rocuronium 0.6 mg kg-1 neuromuscular block to evaluate NMT diagnostic accuracy in indicating 3 clinically relevant time points namely; MMG T1 5% (95% twitch depression) for tracheal intubation, MMG T1 25% for repeat neuromuscular blocking agents (NMBAs) administration, and MMG 0.9 TOF ratio full neuromuscular block recovery. We compared onset time (time from beginning of rocuronium administration until maximal depression), Dur25 (time until T1 25% recovery) and Dur0.9 (time until 0.9 TOF ratio recovery). In Study-1, NMT showed low sensitivity in indicating MMG time for tracheal intubation, repeat NMBAs administration and full neuromuscular block recovery (6.25%, 38.9% and 38.9% respectively). NMT onset time, Dur25 and Dur0.9 (2:51 ± 00:57, 36:50 ± 24:25, 70:08 ± 25:27 min:s) were significantly longer than MMG (1:56 ± 00:46, 30:26 ± 20:24, 62:03 ± 20:01). In Study-2, NMT onset time, Dur25 and Dur0.9 (02:37 ± 00:53, 35:38 ± 11:54, 53:40 ± 13:49) were not significantly different than WTCH (02:23 ± 00:45, 33:27 ± 12:51, 53:57 ± 12:47). NMT could not efficaciously detect MMG time for tracheal intubation; NMBAs repeat dose administration or full neuromuscular block recovery. Data from NMT cannot be used interchangeably with MMG. Our study revealed that NMT Tri-axial acceleromyography seems to offer no advantage over the MMG gold standard or the classic Mono-axial TOF-Watch SX monitor.

The success of mRNA-based therapies depends on the availability of a safe and efficient delivery vehicle. Lipid nanoparticles have been identified as a viable option. However, there are concerns whether an acceptable tolerability profile for chronic dosing can be achieved. The efficiency and tolerability of lipid nanoparticles has been attributed to the amino lipid. Therefore, we developed a new series of amino lipids that address this concern. Clear structure-activity relationships were developed that resulted in a new amino lipid that affords efficient mRNA delivery in rodent and primate models with optimal pharmacokinetics. A 1-month toxicology evaluation in rat and non-human primate demonstrated no adverse events with the new lipid nanoparticle system. Mechanistic studies demonstrate that the improved efficiency can be attributed to increased endosomal escape. This effort has resulted in the first example of the ability to safely repeat dose mRNA-containing lipid nanoparticles in non-human primate at therapeutically relevant levels.

Objective: Is a single dose of gonadotropin-releasing hormone agonist (GnRHa) trigger to induce final oocyte maturation in polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization (IVF) cycles with GnRH antagonist protocol sufficient to provide optimal oocyte maturity? Design: This is a prospective, randomized, double-blind, proof-of-concept study. Setting: This study was carried out at a tertiary care center. Material and Methods: A total of 125 patients diagnosed with PCOS defined as per the ESHRE/ASRM Rotterdam criteria (2003) undergoing IVF in antagonist protocol were randomized into two groups. Group A: single dose of GnRHa 0.2 mg, 35 h prior to oocyte retrieval, and Group B: 0.2 mg GnRHa 35 h prior to oocyte retrieval + repeat dose of 0.1 mg 12 h following the 1st dose. 12 h post-trigger, luteinizing hormone (LH), progesterone (P4), and follicle-stimulating hormone (FSH) values were estimated. Statistical Analysis: Continuous variables were expressed as mean ± standard deviation and categorical variables as proportions where applicable. Independent sample t-test was used for continuous variables which were normally distributed and Mann–Whitney U-test for data not normally distributed. Chi-square test or Fisher's exact test was used for categorical variables where appropriate. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated. In addition, receiver operating characteristic curve was used to evaluate the post-trigger LH, P4, and FSH values at 12 h as predictors of oocyte maturity. Main Outcome Measures: Primary outcome: maturity rate of the oocytes. Secondary outcomes: oocyte yield, fertilization rate, availability of good quality embryos on day 3, blastocyst conversion, OHSS rates, post-trigger serum LH (IU/L), FSH (IU/L), and P4 (ng/mL) levels implantation rate and clinical pregnancy rate. Results: A higher number of mature (metaphase II) oocytes were obtained in Group B compared to Group A (OR of 0.47; CI: 0.38–0.57; P < 0.01). Significantly a higher number of blastocysts were obtained in Group B than Group A (4.00 vs. 3.04; P = 0.023). The odds of clinical pregnancy per patient were higher in Group B (OR = 0.56; CI [0.27–1.24]), with a trend towards better clinical pregnancy in Group B than in Group A. Conclusions: A repeat dose of GnRHa trigger 12 h following the first dose probably by maintaining a sustained level of gonadotropins yielded a better maturity of oocytes, higher number of blastocysts, and a trend towards higher clinical pregnancy than a single dose in PCOS patients undergoing IVF in antagonist cycles.

Objective This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazettcorrected QT duration and QTcI outliers Pharmacokinetics and adverse events (AEs) were also assessed. Results Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. Conclusions Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study.

Chitosan is a natural polymer with excellent properties such as biocompatibility, biodegradability, non-toxicity and adsorptive abilities. We obtained chitosan derived from Panurilus argus lobster shell and its lactate and acetate salts to introduce in pharmaceutical industry. We examined the single and repeated dose toxicity of chitosan and its lactate and acetate salts. Single oral doses of 2000 mg/kg were well tolerated for all three materials. In the repeat dose tests, animals treated with chitosan only show a slight erythrocytes increase. Variations in erythrocyte and leukocyte count and some biochemical parameters were observed in animals treated with chitosan acid salts. One g/kg orally was found to be the subacute NOAEL for chitosan due to the hematological findings observed were not considered adverse. Chitosans obtained from Panurilus argus lobster shell have low toxicity and may be safe in rats because it did not cause any lethality or changes in the general behavior in both the single and repeated dose toxicity studies.

Background As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Results Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. Conclusions The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles. Electronic supplementary material The online version of this article (doi:10.1186/s12989-017-0206-4) contains supplementary material, which is available to authorized users.

The current animal-based paradigm for safety assessment must change. In September 2016, the UK National Centre for Replacement, Refinement and Reduction of Animals in Research (NC3Rs) brought together scientists from regulatory authorities, academia and industry to review progress in bringing new methodology into regulatory use, and to identify ways to expedite progress. Progress has been slow. Science is advancing to make this possible but changes are necessary. The new paradigm should allow new methodology to be adopted once it is developed rather than being based on a fixed set of studies. Regulatory authorities can help by developing Performance-Based Standards. The most pressing need is in repeat dose toxicology, although setting standards will be more complex than in areas such as sensitization. Performance standards should be aimed directly at human safety, not at reproducing the results of animal studies. Regulatory authorities can also aid progress towards the acceptance of non-animal based methodology by promoting "safe-haven" trials where traditional and new methodology data can be submitted in parallel to build up experience in the new methods. Industry can play its part in the acceptance of new methodology, by contributing to the setting of performance standards and by actively contributing to "safe-haven" trials.

Aim: We explored the positions of nurses working in hospitals regarding the acceptability of refusing to give a repeat dose of painkiller to a postoperative patient who requested it. These positions were compared with that of lay people, physicians, and other health professionals. Design and Methods: Factorial design was used to assess the impact of 6 situational factors: the patient's age, the current level of pain as assessed by the nurse, the number of requests, the level of risk associated with the administration of a repeat dose, the outcome of surgery, and the giving of alternative mild analgesics. We implemented a combination of scenario technique and of cluster analysis. Data were collected from April 2013 to December 2015. Participants: 138 registered nurses, 32 nurse's aides, 33 physicians, 23 psychologists, and 169 lay people participated in the study. Results: We found 4 qualitatively different meaningful positions. A plurality of participants (57% of nurses) considered that refusing was not acceptable, irrespective of circumstances. A substantial minority of participants (but 52% of physicians) considered that refusing was acceptable only if the level of pain was low and the risk was high. Other participants (mostly lay people) considered that refusing was always acceptable each time a risk of side effects, either serious or simply mild, was present.

A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

The repeat-dose and developmental toxicities of certain petroleum refinery streams are related to their polycyclic aromatic compound (PAC) content ( Feuston et al., 1994 ). Building on this foundation, and working within the context of the US EPA High Production Volume (HPV) Chemical Challenge Program, we: (1) characterized relationships between PAC content and repeat-dose and developmental toxicities of high boiling petroleum substances (HBPS), and (2) developed statistical models that can be used to predict critical effects of similar untested substances. Data from 39 dermal toxicity studies of HBPS were used to develop statistical models to predict the dose–response relationships between the weight percent concentration of each of their 1–7 aromatic ring classes and 4 repeat-dose and 3 developmental endpoints (absolute thymus weight, hemoglobin count, platelet count, liver to body weight, live fetus count, fetal weight, and percent resorptions). The correlations between the observed and model-predicted values are >0.90. The predictive ability of the models was tested via a series of evaluation or corroboration methods. As is shown in the paper, using only compositional data of untested HBPS, the models can be used to predict the effect at a given dose or the dose that causes an effect of a stipulated magnitude.

In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects. This work expands the database of chemicals with reproductive and developmental data, presents these data in a comprehensive and transparent format and groups the chemicals according to the TTC "Cramer Class" rules. Distributions of NOAELs from each of these classes were used to assess whether the previously proposed TTC values based on repeat dose data are protective for reproductive/developmental toxicity endpoints as well. The present analysis indicates that, for each Cramer Class, the reproductive and developmental endpoints would be protected at the corresponding general TTC tiers derived by Munro et al. (1996).