Short-term toxicity tests utilizing mitochondrial and microsomal metabolism were developed and applied to a series of eight quinones. In the mitochondrial assay, the degree to which test compounds inhibited mitochondrial respiration varied from an EC50 of 9 μM to l25 μM. In the microsomal assay, the maximum percent increase over control oxygen consumption rates elicited by the quinones ranged from eight percent to 837 percent. The ability of the compounds to stimulate microsomal oxygen uptake reflects their capability to redox cycle and form reactive oxygen species. Experiments were conducted to evaluate the relationship between the rate of quinone redox cycling and the extent of microsomal lipid peroxidation, a possible toxic insult associated with reactive oxygen species. Results of the mitochondrial and microsomal assays were statistically correlated with several quinone physicochemical parameters and qualitatively compared to reduction potential. The biological response observed in both test systems appeared to be most strongly influenced by the reduction potential of the quinone and biomechanisms of action were suggested based on this relationship. To assess the ability of the mitochondrial and microsomal assays to indicate toxicity of the quinonoid compounds, results were statistically correlated with literature-derived toxicity data. It was concluded that the mitochondrial assay appears to be a valid indicator of acute toxicity, while the microsomal assay better portends the potential for chronic toxicity. / Master of Science

The Pacific white leg shrimp, Litopenaeus vannamei, is a potential species for low salinity inland aquaculture. Due to several independent variables, such as species, age, size, salinity and pH, that must be taken into account, there are gaps in the literature pertaining to the toxicity of ammonia and nitrite to shrimp. This study was conducted to investigate the individual and combined effects of ammonia and nitrite on L. vannamei postlarvae (25-45 days old) at 10 ppt salinity, 28 C and a pH of 7.8. The independent variables were salinity, total ammonia as nitrogen (TAN) and nitrite-N (NO₂-N), separately and combined. The TAN experiments were conducted at 18 and 10 ppt salinity while the NO₂-N test was conducted at 10 ppt salinity. Combined TAN and NO2 tests were also conducted at 10 ppt salinity. The LC50 values for TAN at 18 ppt salinity, TAN at 10 ppt salinity, and NO2-N at 10 ppt were observed to be 42.92, 39.72 mg/L (2.26 and 2.09 mg/L unionized ammonia-N), and 153.75 mg/L, respectively. When NO₂- N was adjusted to the LOEC level and TAN concentrations were varied, synergistic effects were observed, with an LC50 calculated to be 28.2 mg/L TAN (1.49 mg/L unionized ammonia-N). However, when the ammonia level was adjusted to the LOEC and nitrite was varied, antagonistic effects were observed with an LC50 calculated to be 163.3 mg/L NO₂-N. The results suggest that further investigations into the combined effects of ammonia and nitrite at varying concentrations and lower salinities will be important in developing "standard operating procedures" for the shrimp industry. / Master of Science

No / The rate at which toxicological data is generated is continually becoming more rapid and the volume of data generated is growing dramatically. This is due in part to advances in software solutions and cheminformatics approaches which increase the availability of open data from chemical, biological and toxicological and high throughput screening resources. However, the amplified pace and capacity of data generation achieved by these novel techniques presents challenges for organising and analysing data output. Big Data in Predictive Toxicology discusses these challenges as well as the opportunities of new techniques encountered in data science. It addresses the nature of toxicological big data, their storage, analysis and interpretation. It also details how these data can be applied in toxicity prediction, modelling and risk assessment.

No / Due to the advance of modern computing technology, decisions can be made based on all the existing related data instances scattered across multiple data storages, such that available information has been entirely taken into consideration. Particularly in the predictive toxicology domain, because of the heterogeneity of data sources, multiple data instances with respect to the same endpoint are usually inconsistent, and the quality (or reliability) of the data instances is typically different. Also, the quantity of data instances is often not sufficient to conduct a study using conventional statistics-based methods. This paper presents a novel risk analysis approach for chemical toxicity assessment which considers all the available heterogeneous data instances in the same time, assisted by their quality (or reliability) values. The system is developed on the basis of possibility-probability distribution, where the uncertainty of the approximated probability values based on traditional statistics methods is represented by possibility. The uncertainty considered herein is led not only by the statistics on limited small number of data instances, but also by the poor quality (or reliability) of data instances. The possibility-probability distribution is automatically computed from available data instances by employing a modified diffused-interior-outer-set model (where the reliability of data is considered) based on information diffusion theory. Toxicity value for a given chemical compound is then estimated as the fuzzy expected value based on the resulted possibility-probability distribution. Toxicity risk with respect to regulatory threshold is also introduced, in order to evaluate the probability of which the toxicity may be classified into a certain regulatory range. The proposed approach is applied to a real-world dataset to illustrate the utility and the potential of the approach in risk assessment of chemical toxicity.

INTRODUCTION: Multiple Myeloma (MM) is a plasma cell malignancy that causes improper production of immunoglobulins and elevated levels of monoclonal protein. Resulting morbidity is a conglomeration of symptoms due to organ failure, lytic bone disease, and hematological insufficiencies. The American Cancer Society estimates more than 35,000 patients will be diagnosed with multiple myeloma in the United States in 2023. Current therapeutic regimen hinge on the idea of myeloma as a chronic disease that cannot be entirely cured and toxic chemotherapies with long-term treatment cycles are the standard of care. The need for a one-time therapy that is both safe and efficacious and with potentially curative action has led to the development of anti-BCMA CAR T-cell infusions. The overwhelming success of this novel therapy in MM has been demonstrated in clinical trials, but the need for data surrounding the long-term toxicities post-CAR T-cell treatment in a real-world population of MM patients still exists. Common expected adverse events that have been identified in clinical trials include cytokine release syndrome, neurotoxic events, hematological toxicities, and infections associated with immunosuppression. This study was formed to elucidate the long-term adverse events associated with anti-BCMA CAR T-cell therapy in a real-world patient population. METHODS: A total of 54 patients who received a CAR T-cell infusion for their relapsed and refractory multiple myeloma were studied in a retrospective analysis at Dana-Farber Cancer Institute. Data were collected prior, during, and after infusion to gauge treatment performance and toxic side effects. Analyses of collected data, including complete blood counts, serum protein electrophoresis, fluorescence in-situ hybridization (FISH) data from bone marrow biopsy, and imaging were performed. RESULTS: Patients were followed for a mean average of 165 days (range 29-462) post-infusion. Patients either received CiltaCel (n = 7) or IdeCel (n = 47). Grade 3 or greater cytopenia occurred in 48% of patients at some point following infusion and the median time to first onset was 30 days (10-189). Forty-six patients (85%) achieved a partial response or better as their best response to therapy. During inpatient infusion, 76% of patients experienced grade 1 or 2 cytokine release syndrome (CRS) and 8% experienced grade 1 or 2 immune effector cell-associated neurotoxicity syndrome (ICANS). A total of 12 patients (22%) developed infections after infusion with respiratory infections being the most frequent (17%). Nine patients were also evaluated on a closer scale for their experience with prolonged cytopenia, but no significant commonalities were found. DISCUSSION: The analysis of this study found this patient population to have a considerably less frequent incidence of high grade cytopenia as compared to clinical trial data. However, 92% of patients developed grade 1-3 anemia and 77% developed any grade thrombocytopenia, both figures are greater than those presented in the KarMMa-2 clinical trial study for ide-cel. Patients who developed severe cytopenia were able to recover absolute neutrophil counts (ANC) over the course of their follow-up appointments which is an important aspect in the prevention and avoidance of serious infection. This same recovery was not observed in platelet or hemoglobin counts. Additionally, 15 patients were reported to still have high-grade cytopenia at 30—60-days post infusion, but this number drops to only 5 patients for the 60—90-day timeframe, this steep drop is indicative of an early onset of severe cytopenia that may not carry on as the patient progresses further from their infusion date. Compared to the KarMMa-2 study which reported an infection incidence of 69%, observations from this current study suggest this real-world patient population remained healthier after infusion in terms of infection with only 23% of patients developing post-infusion infection. Instances of CRS and ICANS were comparable to data evaluated in clinical trials. Finally, treatment responses did not significantly differ between the population of patients who developed grade 3 or greater cytopenia and those patients who did not. More data is required to determine the risk-benefit profile of early intervention with CAR T-cell therapy as directly compared to the current standard of care. This study is an encouraging insight into the performance of real-world RRMM patients that should assure patients and clinicians of the safety and uncompromising efficacy of anti-BCMA therapy as a treatment option for multiple myeloma.

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