Predicting Hydrocarbon Primary Biodegradation in Soil and Sediment Systems Using System Parameterization and Machine Learning.

Technical complexity associated with biodegradation testing, particularly for substances of unknown or variable composition, complex reaction products, or biological materials (UVCB), necessitates the advancement of non-testing methods such as quantitative structure-property relationships (QSPRs). Models for describing the biodegradation of petroleum hydrocarbons (HCs) have been previously developed. A critical limitation of available models is their inability to capture the variability in biodegradation rates associated with variable test systems and environmental conditions. Recently, the Hydrocarbon Biodegradation System Integrated Model (HC-BioSIM) was developed to characterize the biodegradation of HCs in aquatic systems with the inclusion of key test system variables. The present study further expands the HC-BioSIM methodology to soil and sediment systems using a database of 2195 half-life (i.e., degradation time [DT]50) entries for HCs in soil and sediment. Relevance and reliability criteria were defined based on similarity to standard testing guidelines for biodegradation testing and applied to all entries in the database. The HC-BioSIM soil and sediment models significantly outperformed the existing biodegradation HC half-life (BioHCWin) and virtual evaluation of chemical properties and toxicities (VEGA) quantitative Mario Negri Institute for Pharmacological Research (IRFMN) models in soil and sediment. Average errors in predicted DT50s were reduced by up to 6.3- and 8.7-fold for soil and sediment, respectively. No significant bias as a function of HC class, carbon number, or test system parameters was observed. Model diagnostics demonstrated low variability in performance and high consistency of parameter usage/importance and rule structure, supporting the generalizability and stability of the models for application to external data sets. The HC-BioSIM provides improved accuracy of Persistence categorization, with correct classification rates of 83.9%, and 90.6% for soil and sediment, respectively, demonstrating a significant improvement over the existing BioHCWin (70.7% and 58.6%) and VEGA (59.5% and 18.5%) models. Environ Toxicol Chem 2024;00:1-12. © 2024 Concawe. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

In Silico Acute Aquatic Hazard Assessment and Prioritization Using a Grouped Target Site Model: A Case Study of Organic Substances Reported in Permian Basin Hydraulic Fracturing Operations.

Hydraulic fracturing (HF) is commonly used to enhance onshore recovery of oil and gas during production. This process involves the use of a variety of chemicals to support the physical extraction of oil and gas, maintain appropriate conditions downhole (e.g., redox conditions, pH), and limit microbial growth. The diversity of chemicals used in HF presents a significant challenge for risk assessment. The objective of the present study is to establish a transparent, reproducible procedure for estimating 5th percentile acute aquatic hazard concentrations (e.g., acute hazard concentration 5th percentiles [HC5s]) for these substances and validating against existing toxicity data. A simplified, grouped target site model (gTSM) was developed using a database (n = 1696) of diverse compounds with known mode of action (MoA) information. Statistical significance testing was employed to reduce model complexity by combining 11 discrete MoAs into three general hazard groups. The new model was trained and validated using an 80:20 allocation of the experimental database. The gTSM predicts toxicity using a combination of target site water partition coefficients and hazard group-based critical target site concentrations. Model performance was comparable to the original TSM using 40% fewer parameters. Model predictions were judged to be sufficiently reliable and the gTSM was further used to prioritize a subset of reported Permian Basin HF substances for risk evaluation. The gTSM was applied to predict hazard groups, species acute toxicity, and acute HC5s for 186 organic compounds (neutral and ionic). Toxicity predictions and acute HC5 estimates were validated against measured acute toxicity data compiled for HF substances. This case study supports the gTSM as an efficient, cost-effective computational tool for rapid aquatic hazard assessment of diverse organic chemicals. Environ Toxicol Chem 2024;43:1161-1172. © 2024 ExxonMobil Petroleum and Chemical BV. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

US and international per- and polyfluoroalkyl substances surface water quality criteria: A review of the status, challenges, and implications for use in chemical management and risk assessment.

Regulation of per- and polyfluorinated substances (PFAS) in surface water is a work-in-progress with relatively few criteria promulgated in the United States and internationally. Surface water quality criteria (SWQC) or screening values derived for perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) by Australia, Canada, the European Union (EU), and four US states (Florida, Michigan, Minnesota, and Wisconsin), and the San Francisco Bay Regional Water Quality Control Board (SFB RWQCB; California) were compared. Across these eight jurisdictions, promulgated numeric criteria for the same compound and receptor span over five orders of magnitude as a result of different approaches and data interpretations. Human health criteria for PFOS range from 0.0047 to 600 ng/L depending on route of exposure (e.g., fish consumption or drinking water) and are lower than most ecological criteria for protection of aquatic and wildlife receptors. Data gaps and uncertainty in chronic toxicity and bioaccumulation of PFOS and PFOA, as well as the use of conservative assumptions regarding intake and exposure, have resulted in some criteria falling at or below ambient background concentrations and current analytical detection limits (around 1 ng/L for commercial laboratories). Some jurisdictions (e.g., Australia, Canada) have deemed uncertainty in quantifying water-fish bioaccumulation too great and set fish tissue action levels in lieu of water criteria. Current dynamics associated with the emerging and evolving science of PFAS toxicity, exposure, and environmental fate (i.e., data gaps and uncertainty), as well as the continuous release of scientific updates, pose a challenge to setting regulatory limits. Integr Environ Assess Manag 2024;20:36-58. © 2023 AECOM Technical Services, Inc and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Using weight of evidence to assess degradation potential of UVCB hydrocarbon solvents.

Hydrocarbon solvents are a diverse group of petrochemical substances that are identified as unknown or variable composition, complex reaction products, or biological materials (UVCBs) and may contain tens of thousands of individual chemical constituents. As such, it is generally not possible to analytically resolve every chemical constituent in a hydrocarbon solvent. This, along with the low water solubility and/or high vapor pressure of constituents, precludes the use of many standardized tests designed to determine biodegradation in the environment (e.g., Organization for Economic Co-operation and Development [OECD] 309). A weight of evidence approach may be needed to reduce uncertainty to an acceptable level such that a determination on the biodegradation of the substance can be drawn. Based on the OECD 2019 weight of evidence guidance, we present a framework using various lines of evidence that can be used to evaluate the biodegradation of a UVCB solvent in a weight of evidence approach. The lines of evidence include whole substance testing, data on representative constituents, quantitative structure activity relationship (QSAR) models, and biological plausibility. Using these lines of evidence, "Hydrocarbon, C11-C14, normal alkane, isoalkane, cyclic, <2% aromatics" (EC# 926-141-6) was evaluated in a case study. Data from three whole substance tests, 43 constituents (representing 152 data points), three QSAR models and evidence of microbial degradation pathways were evaluated. Based on the available data, it is concluded that the solvent for the case study is not expected to persist in the environment. This framework sets out a real-world example of how the weight of evidence can be used to evaluate hydrocarbon solvents. While focused on persistence, similar approaches can be used to evaluate other endpoints such as bioaccumulation and toxicity. Integr Environ Assess Manag 2023;19:1120-1130. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person). OBJECTIVE: The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy. METHODS: This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy. RESULTS: The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy. CONCLUSIONS: The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials.

BACKGROUND: Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. OBJECTIVE: Analyses evaluated the time to onset of clinical response during treatment with pitolisant. METHODS: Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo. RESULTS: The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]). CONCLUSIONS: Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS. GOV IDENTIFIER: NCT01067222 (February 2010), NCT01800045 (February 2013).

Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term, placebo-controlled studies.

STUDY OBJECTIVE: To evaluate the efficacy of pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms. METHODS: Data were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week. RESULTS: The analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) compared with placebo (-0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant. CONCLUSIONS: Pitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.

Bioaccumulation potential of naphthenic acids and other ionizable dissolved organics in oil sands process water (OSPW) - A review.

Bitumen recovery via mining in Alberta's Athabasca region generates large quantities of oil sands process water (OSPW). Aquatic toxicity of OSPW has been well-studied and the class of organic compounds referred to as naphthenic acids (NAs) are consistently implicated as the primary driver. Proposed lease closure options include treated produced waters in reclaimed landscapes such as pit lakes and wetlands. Consequently, it is crucial to understand the bioaccumulation potential of NAs and other OSPW dissolved organics in these environments. Early studies were focussed only on NAs due to analytical limitations, however, later studies investigated additional classes of dissolved organics in OSPW. Reported bioconcentration factors (BCFs) for NAs in fish and amphibians range from 0.24 to 53 L/kg wet-weight. Most quantitative assessments of NAs bioaccumulation potential evaluated commercial NAs mixtures as a surrogate for OSPW and used using single-ion monitoring for measuring NAs concentrations. The resulting BCF values are based on the NA isomers that conform to the formula, C13H22O2. More recently, an advanced analytical technique capable of determining the profile of different isomer classes in OSPW showed that NAs and other OSPW ionizable dissolved organics (OSPW-IDO) have low partitioning to simulated biological storage lipids, suggesting low bioaccumulation potential. Using the same analytical technique to assess in vivo fish exposures, a subsequent study reported a range of BCFs for OSPW NAs between 0.7 and 53 L/kg wet-weight and heteroatomic isomer classes containing S or N heteroatoms had BCFs between 0.6 and 28 L/kg wet-weight. Reported BCFs for all isomer classes of the OSPW-IDO fraction were less than the Canadian standard for bioaccumulative designation (i.e., BCF ≥ 5000).

Retrospective review of the efficacy and safety of repeated pulsed and continuous radiofrequency lesioning of the dorsal root ganglion/segmental nerve for lumbar radicular pain.

BACKGROUND: Chronic lumbosacral radicular pain is a common source of radiating leg pain seen in pain management patients. These patients are frequently managed conservatively with multiple modalities including medications, physical therapy, and epidural steroid injections. Radiofrequency has been used to treat chronic radicular pain for over 30 years; however, there is a paucity of literature about the safety and efficacy of repeat radiofrequency lesioning. OBJECTIVES: To determine the safety, success rate, and duration of pain relief of repeat pulsed radiofrequency (PRF) and continuous radiofrequency (CRF) lesioning of the dorsal root ganglion (DRG)/ sacral segmental nerves (SN) in patients with chronic lumbosacral radicular pain. STUDY DESIGN: Retrospective chart review SETTING: Outpatient multidisciplinary pain center METHODS: Medical record review of patients who were treated with pulsed and continuous radiofrequency lesioning of the lumbar dorsal root ganglia and segmental nerves and who reported initial success were evaluated for recurrence of pain and repeat radiofrequency treatment. Responses to subsequent treatments were compared to initial treatments for success rates, average duration of relief, and adverse neurologic side-effects. LIMITATIONS: Retrospective chart review without a control group. RESULTS: Twenty-six women and 24 men were identified who received 50% pain relief or better after PRF and CRF of the lumbar DRG/ sacral SN for lumbosacral radicular pain. The mean age was 62 years (range, 25-86). The mean duration of relief for the 40 patients who had 2 treatments was 4.7 months (range 0-24; Se [standard error] 0.74). Twenty-eight patients had 3 treatments with an average duration of relief of 4.5 months (range 0-19 months; Se 0.74). Twenty patients had 4 treatments with a mean duration of relief of 4.4 months (range 0.5-18; Se 0.95) and 18 patients who had 5 or more treatments received an average duration of relief of 4.3 months (range 0.5-18; Se 1.03). The average duration of relief and success frequency remained constant after each subsequent radiofrequency treatment. Of the 50 total patients, there was only 1 reported complication, specifically, transient thigh numbness which resolved after one week. CONCLUSIONS: Repeated pulsed and continuous radiofrequency ablation of the lumbar dorsal root ganglion/segmental nerve shows promise to be a safe and effective long-term palliative management for lumbosacral radicular pain in some patients.

Cognitive disparity in schizophrenics with and without cocaine dependency.

Although cognition has been investigated in individuals with schizophrenia and in non-schizophrenic cocaine abusers, few studies have focused on cocaine-abusing schizophrenics. Previous studies have shown contradictory results despite the fact that individuals with schizophrenia and cocaine dependence have worse long-term outcomes, and that each disorder separately is associated with neuropsychological impairment. The present study intended to clarify these inconsistencies with a comprehensive neuropsychological battery. Twenty-four cocaine-dependent schizophrenics and 23 non-drug abusing schizophrenics were recruited from the VA. Participants were administered tests focusing on motor skills, processing speed, attention, concentration, and executive functioning. While individuals with schizophrenia and cocaine dependence performed worse on the Grooved Peg Board and the Stroop A, the non-drug abusing schizophrenics performed worse on Trails Part A and B. However, a MANOVA failed to show group differences in overall neuropsychological performance. These findings are similar to the existing literature and suggest that cocaine may compromise motor functioning.

Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence.

OBJECTIVE: To examine the efficacy of atypical neuroleptics for decreasing craving and drug relapses during protracted withdrawal in individuals dually diagnosed with schizophrenia and cocaine dependence. METHOD: We conducted a 6-week, open-label pilot study comparing risperidone with typical neuroleptics in a sample of withdrawn cocaine-dependent schizophrenia patients. RESULTS: Preliminary results suggest that individuals treated with risperidone had significantly less cue-elicited craving and substance abuse relapses at study completion. Further, they showed a trend toward a greater reduction in negative and global symptoms of schizophrenia. CONCLUSION: Atypical neuroleptics may help reduce craving and relapses in this population. Future research should include more rigorous double-blind placebo-controlled studies with this class of medications.