An integrated assessment of the 1,4-dioxane cancer mode of action and threshold response in rodents.

1,4-Dioxane is an environmental contaminant that has been shown to cause cancer in rodents after chronic high dose exposures. We reviewed and integrated information from recently published studies to update our understanding of the cancer mode of action of 1,4-dioxane. Tumor development in rodents from exposure to high doses of 1,4-dioxane is preceded by pre-neoplastic events including increased hepatic genomic signaling activity related to mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity. These events are followed by regenerative repair and proliferation and eventual development of tumors. Importantly, these events occur at doses that exceed the metabolic clearance of absorbed 1,4-dioxane in rats and mice resulting in elevated systemic levels of parent 1,4-dioxane. Consistent with previous reviews, we found no evidence of direct mutagenicity from exposure to 1,4-dioxane. We also found no evidence of CAR/PXR, AhR or PPARα activation resulting from exposure to 1,4-dioxane. This integrated assessment supports a cancer mode of action that is dependent on exceeding the metabolic clearance of absorbed 1,4-dioxane, direct mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity followed by sustained proliferation driven by regenerative repair and progression of heritable lesions to tumor development.

A 90-day drinking water study in mice to characterize early events in the cancer mode of action of 1,4-dioxane.

Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse. Therefore, we conducted a 90-day drinking water study in female mice to evaluate early KE at 7, 28, and 90 days. Female B6D2F1/Crl mice consumed drinking water containing 0, 40, 200, 600, 2000 or 6000 ppm 1,4-DX. 1,4-DX was detected in blood at 90-days of exposure to 6000 ppm, but not in the other exposure groups, indicating a metabolic clearance threshold between 2000 and 6000. Early events identified in this study include glycogen-like vacuolization, centrilobular hypertrophy, centrilobular GST-P staining, apoptosis, and pan-lobular increase in cell proliferation observed after 90-days of exposure to 6000 ppm 1,4-DX. There was minimal evidence of hepatotoxicity over the duration of this study. These findings demonstrate a previously unreported direct mitogenic response following exposures exceeding the metabolic clearance threshold of 1,4-DX. Collectively, the information generated in this study supports a threshold MOA for the development of liver tumors in mice after exposure to 1,4-DX.

Environmental exposure to perchlorate: A review of toxicology and human health.

Perchlorate pharmacology and toxicology studies date back at least 65 years in the peer-reviewed literature. Repeated studies in animals and humans have demonstrated perchlorate's mechanism of action, dose-response, and adverse effects over a range of doses. The first measurable effect of perchlorate is inhibition of iodine uptake to the thyroid gland. Adequate levels of thyroid hormones are critical for the development of the fetal nervous system. With sufficient dose and exposure duration, perchlorate can reduce thyroid hormones in the pregnant or non-pregnant woman via this mechanism. The developing fetus is the most sensitive life stage for chemical agents that affect iodide uptake to the thyroid. Perchlorate has a half-life of eight hours, is not metabolized, does not bioaccumulate, is not a mutagen or carcinogen, and is not reprotoxic or immunotoxic. More recently, epidemiological and biomonitoring studies have been published in the peer-reviewed literature characterizing the thyroidal effects of perchlorate and other goitrogens. While the results from most populations report no consistent association, a few studies report thyroidal effects at environmentally relevant levels of perchlorate. We reviewed the literature on health effects of perchlorate at environmental exposure levels, with a focus on exposures during pregnancy and neurodevelopmental effects. Based on the studies we reviewed, health effects are expected to only occur at doses substantially higher than environmental levels.

Determination of Thresholds of Radioactive Iodine Uptake Response With Clinical Exposure to Perchlorate: A Pooled Analysis.

OBJECTIVE: To conduct a more robust examination of perchlorate exposure on iodide uptake inhibition (IUI) using pooled data from four clinical studies of perchlorate exposure. METHODS: To establish a response threshold for IUI, data were analyzed using segmented linear regression and benchmark dose (BMD) analysis. RESULTS: Segmented linear regression applied to data for 69 subjects representing nine doses identified a breakpoint corresponding to a change in the slope of the dose-response relationship of 3.0 mg/d perchlorate. The estimated BMD for a 20% decrease in iodine uptake was 2.3 mg/d, with a lower 95% confidence interval limit of 1.6 mg/d. CONCLUSIONS: A threshold dose for IUI from perchlorate exposure of 1.6 to 3.0 mg/d (0.021 to 0.038 mg/kg d) was estimated using two modeling approaches. These estimates are slightly higher than the lowest observed effect level of 0.02 mg/kg d from the Greer Study.

Exposure of the US Population to Nitrate, Thiocyanate, Perchlorate, and Iodine Based on NHANES 2005-2014.

Perchlorate, thiocyanate, nitrate, and iodide all have the same action of iodide uptake inhibition. Urinary samples were available for the US population through the National Health and Nutrition Examination Survey (NHANES) database for these compounds and were evaluated for the 2005 through 2014 time period. We were interested in whether exposures to the US population had changed since the mid-2000s. Given that these exposures were largely naturally derived and exposure was from food, we hypothesized that the levels of nitrate, thiocyanate, and perchlorate remained relatively stable over this time period. Additionally, we evaluated mean perchlorate equivalent concentrations (PEC) of all three goitrogens together. There was a significant decrease in urinary perchlorate from 2005 to 2014 (p < 0.01). Thiocyanate and iodide also decreased significantly (p < 0.01), but not nitrate (p = 0.35). PEC decreased since 2005 with contribution from perchlorate at less than 1%, while nitrate increased in contribution.

A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia.

OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD: An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions-Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS: The PANSS total score (mean ± standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 ± 1.8 (P < .001) and -11.9 ± 1.8 (P < .001), respectively. Significant (P ≤ .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS: Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15.

Urinary nitrate, thiocyanate, and perchlorate and serum thyroid endpoints based on NHANES 2001 to 2002.

OBJECTIVE: To determine, on the basis of iodide uptake inhibition (IUI), whether associations between urinary concentrations of IUI agents (perchlorate, nitrate, and thiocyanate), as total perchlorate equivalent concentration (PEC), and serum thyroid parameters suggest functional thyroid abnormalities. Additional thyroid hormone measures were released to augment the National Health and Examination Survey (NHANES) 2001 to 2002 data set, which we used in this study. METHODS: Enhanced thyroid hormone measures released to augment the National Health and Examination Survey (NHANES) 2001-2002 data set were used in this study. Multiple regression was used to assess the relationships among total thyroxine (TT4), free thyroxine, total triiodothyronine (TT3), free triiodothyronine, and thyroid- stimulating hormone (TSH) and PEC. RESULTS: PEC was weakly and negatively associated with TT4, but not with TSH, TT3, or free hormone. This association with TT4 appears to be dominated by nitrate and thiocyanate. CONCLUSION: No evidence of functional thyroid abnormality (eg., low thyroid hormone coupled with high TSH) was seen with exposure to the combined IUI agents and enhanced estimates of thyroid function.

Nanotoxicology and nanomedicine: making hard decisions.

Current nanomaterial research is focused on the medical applications of nanotechnology, whereas side effects associated with nanotechnology use, especially the environmental impacts, are not taken into consideration during the engineering process. Nanomedical users and developers are faced with the challenge of balancing the medical and societal benefits and risks associated with nanotechnology. The adequacy of available tools, such as physiologically-based pharmacokinetic modeling or predictive structure-activity relationships, in assessing the toxicity and risk associated with specific nanomaterials is unknown. Successful development of future nanomedical devices and pharmaceuticals thus requires a consolidated information base to select the optimal nanomaterial in a given situation--understanding the toxicology and potential side effects associated with candidate materials for medical applications, understanding product life cycle, and communicating effectively with personnel, stakeholders, and regulators. This can be achieved through an innovative combination of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (MCDA).

Heart-rate variability in the apolipoprotein E knockout transgenic mouse following exposure to Seattle particulate matter.

Epidemiological studies show that the elderly and/or people with preexisting cardiovascular disease (CVD) are more susceptible to the adverse effects of ambient air pollution. Heart-rate variability (HRV) measured through electrocardiogram (ECG) is a sensitive and effective tool for monitoring the adverse effects of particulate matter (PM). Common HRV parameters used include the standard deviation of the interval between normal beats (SDNN), square root of the mean of the squared differences between normal beats (rMSSD), and distinct high, low, and very low components of frequency. Aged apolipoprotein E knockout transgenic mice, a model of CVD, were implanted with miniaturized ECG telemetry devices and intranasally exposed to saline, 50 microg Seattle PM(2.5) (PM having a mean aerodynamic diameter of < or = 2.5 microm), or silica. They were monitored for a 1-d baseline prior to and for 4 d following exposure. After an initial increase in both heart rate and activity in all groups, there was delayed bradycardia with no change in activity of the animals in the PM- and silica-exposed groups. In addition, with PM and silica exposure there was a decrease in HRV parameters, suggesting a decrease in parasympathetic tone, which may lead to cardiac arrhythmia and mortality. Seattle PM is a toxic species that modulates the autonomic nervous system in a mouse model of CVD.