Comparative Toxicity Research Articles

Comparative reproductive toxicity of phthalate on male and female reproductive potential of rodent when exposure occurs during developmental period

Phthalates are esters of 1, 2-dibenzene dicarboxylic acid, widely used in a variety of commodities such as vinyl flooring, lubricants, and various personal-care products like soaps, shampoos, hair sprays, etc. Phthalates are also used as plasticizers in polyvinyl chloride (PVC) polymers, which helps to make the plastics softer and more durable. Because of their widespread use, both adults and children get exposed to them. Given the fact that phthalates are not chemically bonded to the plastic matrix, they can leak out and pollute the environment around the plastic matrix.Number of studies have indicated that phthalate exposure relates to significant health hazards, including developmental and reproductive damage. Phthalates, according to the findings of the current review, are toxic to the reproductive organs of both male and female fetuses and weanlings when they get exposed during the pregnancy. Several studies have shown that organisms in their growth and developmental stages are especially sensitive to the harmful effects of chemicals, which may have a severe influence on the physiology of foetuses and young animals. Moreover, parameters such as age, gender, immunity, and other variables influence the impact of toxicants. When it comes to male reproductive organs, phthalates have mostly been found to have an adverse impact. While in adult females only few research studies have found harmful effects on female reproductive system. Phthalates have been shown to cause reduced fertility, decreased testicular weight, changes in accessory reproductive organs, and a variety of other female reproductive diseases, among other effects. These findings include an examination of mice female and male reproductive potential, as well as the impact of phthalates on their respective reproductive capabilities when exposure occurs during the formative stage of development.

Comparative toxicity of hydrocarbons for evaluation of Lysmata boggessi as an experimental proxy for deep-water column micronekton

The potential impacts of sub-surface hydrocarbon plumes to deep-water column micronekton are an important consideration in a more complete understanding of ecosystem effects resulting from deep-sea oil spills. However, evaluating toxicity in these organisms presents multiple challenges, and the use of a shallow-water proxy species allows comparison and validation of experimental results. This study thus examined the suitability of the peppermint shrimp, Lysmata boggessi, as an experimental proxy for ecologically important deep-sea zooplankton/micronekton in hydrocarbon toxicity assays. This crustacean species occurs in shallow coastal marine environments throughout the western Atlantic, Caribbean and Gulf of Mexico, is similar in size to the mesopelagic organisms previously tested and is readily available via commercial aquaculture. The effects of 1-methylnaphthalene and fresh Macondo oil (MC252) on L. boggessi were assessed in 48-h constant-exposure toxicity tests, and acute thresholds were compared to previously determined LC50s for oceanic mid water Euphausiidae, Janicella spinacauda, Systellaspis debilis, Sergestes sp., Sergia sp. and the mysid shrimp Americamysis bahia. Acute thresholds and the calculated critical target lipid body burden (CTLBB) for the shallow-water L. boggessi were comparable to the deep-water species tested, suggesting that L. boggessi may be a suitable proxy for some mesopelagic micronekton species in acute hydrocarbon exposures.

Comparative Toxicity of Aqueous and Methanolic Extracts of Brown Macroalgae against Tobacco Cutworm, Spodoptera litura Fabricius

The present study aimed to find the toxicity of aqueous and methanol extracts of three different brown macroalgae viz., Padina tetrastromatica, Sargassum wightii and Turbinaria conoides against tobacco cutworm, Spodoptera litura. Larval mortality was noticed in both the extracts at all the concentrations tested in a dose-dependent increase after 96 h of exposure with 73.33, 56.66, and 50.00 per cent in aqueous extract; and 50.00, 46.66 and 43.33 per cent in methanol extracts at 10 % concentration in S. wightii, T. conoides and P. tetrastromatica, respectively. Pre-pupal and pupal mortality were recorded in all the concentrations showing malformations during the growth. Pupation and adult emergence were also affected by the extracts of S. wightii. From the results, it is surmised that brown macroalgae possess insecticidal potential and growth inhibitory properties which can be exploited for eco-friendly management of Spodoptera litura and possibly other lepidopteran larvae as well.

In vitro assessment of stearyl triphenyl phosphonium toxicity in drug-resistant tumor cells

Introduction: The triphenyl phosphonium residue is a well-documented mitochondriotropic that has been shown to improve the accumulation of biomolecules in mitochondria. Stearyl triphenyl phosphonium (STPP) modified liposomes have been shown to facilitate the selective accumulation of various biomolecules in mitochondria resulting in improved effect in-vitro and in-vivo. More recently, STPP was reported to have higher toxicity towards a drug resistant ovarian cancer cell line compare to a non-drug resistant cell line. The purpose of this study was to further investigate STPP toxicity using multiple drug resistant and non-drug resistant cell lines. Methods: STPP was incorporated into phosphatidylcholine cholesterol liposomes using the thin film hydration method. Mean particle size and zeta potential was measured using dynamic light scattering. The 5,5,6,6′-tetrachloro-1,1′,3,3′ tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) dye accumulation assay was used as an indicator of mitochondrial membrane potential in the tested cell lines. Cytotoxicity of the preparations towards different cell lines was determined using light microscopy and the CellTiter 96® AQueous One Solution Cell Proliferation assay. Results: The JC-1 accumulation assay confirmed that the drug-resistant cell lines had significantly higher dye accumulation than the non-drug resistant cell lines. Higher cytotoxicity of STPP towards drug resistant cell line was seen when incorporated into liposomes but not when dissolved in dimethyl sulfoxide (DMSO). STPP showed a comparable toxicity profile to the known oxidative phosphorylation uncoupler carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone (FCCP). Discussion: Taken together, the data suggest that higher STPP toxicity in the drug-resistant cell lines is influenced by the presence of liposomal lipids and that STPP acts in a way similar to an oxidative phosphorylation uncoupler and is therefore more toxic to the drug-resistant cells that rely on a higher mitochondrial membrane potential to maintain their viability.

Evaluation of Selected Chemicals used for Oil and Gas Production and Their Toxic Effects on the Niger Delta Fresh Water Tilapia Guineensis

There are projections of continuous increase in the world’s energy demand, which might result to increase in oil and gas exploration and production activities. Nigeria for instance, runs a mono-economy that largely depends on the revenues from her rich oil and gas deposits. Oil and gas exploration and production activities are expected to increase over the years in Nigeria to meet her economic needs, as well as the global energy need. However, oil and gas production activities are associated with environmental concerns, especially with respect to management of the kind of wastes it generates. A major waste generated during oil and gas completion and production operations is the Produced Water (composed of water, different production chemicals and other constituents). This study is focused on evaluation of the toxic effects of selected production chemicals on the Niger Delta freshwater Tilapia guineensis. Among the chemicals evaluated include: SPECTRUS NX1173 (Biocide), FLOGARD MS 6208 (Corrosion inhibitor), ELIMINOX (Oxygen scavenger) and EC9017A (anti-foam), while Tilapia guineensis was used as the bioindicator. Whereas there are past researches on the individual chemicals and confirmation that they are toxic in nature, there are no adequate researches on the comparative toxicity effects of these chemicals, especially on the Niger Delta environment. Produced water samples were simulated in the laboratory using the production chemicals (at different concentrations) and 2000ml of freshwater sample for each experimental setup. The fishes were acclimatized for ten days using same freshwater sample, those that survived were selected for the experiment. The mortality and survival rate of the test organism was monitored at a constant interval of one (1) hour for Ninety-six (96) hours and the percentage mortality of the test organism recorded for all the chemicals at different concentrations ranged from 100% to 10%. The lethal concentration (LC50) calculated for each of the chemicals are as follows: Corrosion inhibitor 0.002%, biocide 0.003%, oxygen scavenger 0.01% and defoamer 0.176%. The corrosion inhibitor was the most toxic as there was 100% mortality of the Tilapia guineensis within 24 hours of the test period, while the defoamer was the least toxic as there were more survival of the test organism at the end of the test period. The test results indicated that all the production chemicals used in this research were toxic, their lethal concentrations differed from one chemical to the other, and the corrosion inhibitor and biocide had the highest toxicity effect on the organisms. The research findings could be used as a basis by the Nigerian regulatory agencies for possible review of currently approved completion and production chemicals for oil and gas activities, as well as produced water disposal options, especially discharge in water bodies in the Niger Delta.

Comparative Toxicity Analyses from Different Endpoints: Are New Cyclic Disinfection Byproducts (DBPs) More Toxic than Common Aliphatic DBPs?

In recent years, dozens of halogenated disinfection byproducts (DBPs) with cyclic structures were identified and detected in drinking water globally. Previous in vivo toxicity studies have shown that a few new cyclic DBPs possessed higher developmental toxicity and growth inhibition rate than common aliphatic DBPs; however, in vitro toxicity studies have proved that the latter exhibited higher cytotoxicity and genotoxicity than the former. Thus, to provide a more comprehensive toxicity comparison of DBPs from different endpoints, 11 groups of cyclic DBPs and nine groups of aliphatic DBPs were evaluated for their comparative in vitro and in vivo toxicity using human hepatoma cells (Hep G2) and zebrafish embryos. Notably, results showed that the in vitro Hep G2 cytotoxicity index of the aliphatic DBPs was nearly eight times higher than that of the cyclic DBPs, whereas the in vivo zebrafish embryo developmental/acute toxicity indexes of the cyclic DBPs were roughly 48-50 times higher than those of the aliphatic DBPs, indicating that the toxicity rank order differed when different endpoints were applied. For a broader comparison, a Pearson correlation analysis of DBP toxicity data from nine different endpoints was conducted. It was found that the observed Hep G2 cytotoxicity and zebrafish embryo developmental/acute toxicity in this study were highly correlated with the previously reported in vitro CHO cytotoxicity and in vivo toxicity in aquatic organisms (P < 0.01), respectively. However, the observed in vitro toxicity had no correlation with the in vivo toxicity (P > 0.05), suggesting that the toxicity rank orders obtained from in vitro and in vivo bioassays had large discrepancies. According to the observed toxicity data in this study and the candidate descriptors, two quantitative structure-activity relationship (QSAR) models were established, which help to further interpret the toxicity mechanisms of DBPs from different endpoints.

Evaluation of Comparative Dermal Toxicity and Efficacy of Aargwadhadi Oil and Aargwadhadi Ointment

Introduction: Skin diseases are among the most common of all health illness in recent years, In Ayurveda, management of skin diseases includes internal and external administration. External administration includes various topical applications However, herbal medicines are not completely safe from adverse effects and develop irritation, rashes, redness and burning sensation on the skin as observed in recent researches.“Hence there is a requirement of a safe drug which should be economical &amp; affordable for all. Hence present study is undertaken to study dermal toxicity profile Aargwadhadi oil and Aargwadhadi ointment in an experimental animal and make available safe and efficient drug to the human being.&#x0D; Aim and Objective: Pharmaceutical development, standardization and evaluation of acute, sub-acute dermal toxicity and efficacy of a Aargwadhadi oil and Aargwadhadi ointment and compare efficacy and safety of Aargwadhadi oil and Aargwadhadi ointment.&#x0D; Materials and Methods: Aargwadhadioil and Aargwadhadi Ointment will be prepared as per classical reference and it will be converted into ointment form. Analytical study for standardization of Aargwadhadi oil and Aargwadhadi ointment will be done. Evaluation of Acute and sub-acute dermal toxicity study in experimental animals of both dosage forms as well, efficacy study of Aargwadhadi oil and Aargwadhadi ointment on animal model of vitiligo will be done.&#x0D; Observations and Results: Observation will be done on the basis of assessment criteria evaluation of control group and experimental group will be noted. Results will be drawn on the basis of observations and applying suitable tests. It will be noted and presented in form of table, charts, graphs etc.&#x0D; Conclusion: Conclusion of the study will be drawn accordingly from the recorded observations, analysis of data.

Comparative toxicity, phytochemistry, and use of 53 Philippine medicinal plants

The study compares the toxicity of 53 selected medicinal plants commonly used in the Philippines to treat various diseases. It uses as a benchmark Vitex negundo L., which was approved by the Philippine Food and Drug Administration as an herbal drug for cough and asthma after passing clinical trials for safety and efficacy. The methods were chosen for their simplicity and accessibility even for resource-limited laboratories. Extracts (95 % ethanol) of the medicinal parts of the plants were (1) chemically profiled using qualitative phytochemical tests that detect the presence of key classes of bioactive compounds; and (2) evaluated for toxicity using the brine shrimp (Artemia sp.) lethality assay (BSLA). General phytochemical screening revealed the presence of tannins in 50 plant extracts, alkaloids in 43, glycosides in 33, flavonoids in 31, steroids in 21, triterpenoids in 20, anthraquinones in 10, and saponins in 8. Extracts from eight plants had LC50 values lower than the potassium dichromate control (approximately 12 μg/mL) and were considered highly toxic; extracts from 21 plants had LC50 values between 12 μg/mL and 100 μg/mL and were considered moderately toxic; extracts from 19 plant extracts, including Vitex negundo and some common vegetables, had LC50 values between 100 μg/mL and 500 μg/mL, and were considered mildly toxic and likely to have reasonable safety margins; five plant extracts, including common vegetables, had LC50 values above 500 μg/mL and were considered essentially nontoxic. No apparent correlation could be found between toxicity and chemical diversity or a specific class of phytochemicals present. Our findings may serve as a guide for herbal drug and nutraceutical development, especially in prioritizing plants for more detailed safety studies.

Comparative chronic toxicities of PFOS and its novel alternatives on the immune system associated with intestinal microbiota dysbiosis in adult zebrafish

6:2 Chlorinated polyfluorinated ether sulfonate (F-53B) and sodium p-perfluorous nonenoxybenzene sulfonate (OBS) are widely used as perfluorooctane sulfonate (PFOS) alternatives in the Chinese market. Here, adult zebrafish were chronically exposed to 1 μM PFOS, F-53B, and OBS for 21 days to investigate the comparative immunotoxicity of these three per- and polyfluoroalkyl substances (PFAS). PFOS induced more severe oxidative stress in the liver than F-53B and OBS, and these three PFAS induced similar anti-inflammatory effects by repressing the expression of pro-inflammatory cytokines. The intestinal microbiota analysis showed that the relative abundance of Plesiomonas, Aeromonas, Cetobacterium, Shewanella, and Vibrio changed with the same trend in the three PFAS treatment groups. Furthermore, the PFAS increased the expression of hepcidin, muc, the immune-related genes mpo and saa, and decreased the expression of the tight junction-related gene occ in the intestine; moreover, villus height of the intestine was reduced after PFAS exposure, which indicated the functional disruption of the intestine. In particular, the significant correlation between the changed intestinal microbiota and liver and intestinal indicators also suggested the interaction between the immune system and intestinal microbiota. Taken together, our results indicate that exposure to PFOS and its alternatives F-53B and OBS can induce hepatic immunotoxicity associated with intestinal microbiota dysbiosis in adult zebrafish.

Viability of cultured human skin cells treated with 1,6-hexamethylene diisocyanate monomer and its oligomer isocyanurate in different culture media

The isocyanate monomer 1,6-hexamethylene diisocyanate (HDI) and one of its trimers, HDI isocyanurate, are airway and skin sensitizers contained in polyurethane paint. The toxic response of cultured skin cells to these compounds was measured by evaluating the isocyanate concentrations at which 50% of the cells die (i.e., lethal concentration 50%, LC50) because the relative toxicity of each form of HDI should be considered when exposure limits of HDI-based paints are set. By using a luminescent ATP-viability assay, we compared the cytotoxic effects of HDI monomer and HDI isocyanurate on cultured human skin cells (keratinocytes, fibroblasts, and melanocytes) after 4-h isocyanate exposures using culture media with varying levels of nutrients in order to also determine the effects of media composition on isocyanate toxicity. Before analysis, experimental wells were normalized to controls containing cells that were cultured with the same vehicle and media. The measured mean LC50 values ranged from 5 to 200 µM across the experimental conditions, in which HDI isocyanurate in protein-devoid media was the most toxic to cells, producing the lowest LC50 values. For HDI monomer, keratinocytes were the most resistant to its toxicity and melanocytes were the most susceptible. However, when exposed to HDI isocyanurate, the opposite was observed, with melanocytes being the most resilient and the keratinocytes and fibroblasts were more susceptible. Depending on the type of skin cells, dose–response data indicated that HDI isocyanurate was 2–6 times more toxic than HDI monomer when using protein-devoid media whereas HDI isocyanurate was 4–13 times more toxic than HDI monomer when protein-rich media was used. Therefore, if the protein-devoid saline medium alone were used for these experiments, then a significant under-estimation of their relative toxicities in protein-rich environments would have resulted. This difference is because HDI monomer toxicity was more attenuated by the presence of protein in the culture media than HDI isocyanurate toxicity. Thus, conclusions based on comparative toxicity studies and consequent inference applied to potential human toxicity can be affected by in vitro culture media conditions. The physiochemical difference in reactivity of the two forms of HDI to biological molecules most likely explains the observed toxicity differences and may have implications for skin penetration, adverse effects like skin sensitization, and systemic responses like asthma. Future studies are warranted to investigate differences in the biological availability, cellular toxicity, and immunologic sensitization mechanisms for HDI monomer and HDI isocyanurate.

Association of co-prescribing of opioid and benzodiazepine substitutes with incident falls and fractures among older adults: a cohort study

ObjectiveExamine the association between the co-prescribing of opioids, benzodiazepines, gabapentinoids (pregabalin and gabapentin) and selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors (SSRI/SNRIs) in different combinations and the risk of...

Effects of Bisphenols A, AF, and S on Endochondral Ossification and the Transcriptome of Murine Limb Buds.

Bisphenols are a family of chemicals commonly used to produce polycarbonate plastics and epoxy resins. Exposure to bisphenol A (BPA) is associated with a variety of adverse effects; thus, many alternatives to BPA, such as bisphenol AF (BPAF) and bisphenol S (BPS), are now emerging in consumer products. We have determined the effects of 3 bisphenols on endochondral ossification and the transcriptome in a murine limb bud culture system. Embryonic forelimbs were cultured in the presence of vehicle, BPA, BPAF, or BPS. BPA (≥10 μM), BPAF (≥1 μM), and BPS (≥50 μM) reduced the differentiation of hypertrophic chondrocytes and osteoblasts. Chondrogenesis was suppressed by exposure to ≥50 μM BPA, ≥5 μM BPAF, or 100 μM BPS and osteogenesis was almost completely arrested at 100 μM BPA or 10 μM BPAF. RNA sequencing analyses revealed that the total number of differentially expressed genes increased with time and the concentration tested. BPA exposure differentially regulated 635 genes, BPAF affected 554 genes, whereas BPS affected 95 genes. Although the genes that were differentially expressed overlapped extensively, each bisphenol also induced chemical-specific alterations in gene expression. BPA- and BPAF-treated limbs exhibited a downregulation of Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI) signaling genes. Exposure to BPA and BPS resulted in the upregulation of key genes involved in cholesterol biosynthesis, whereas exposure to BPAF induced an upregulation of genes involved in bone formation and in the p53 signaling pathway. These data suggest that BPAF may be more detrimental to endochondral ossification than BPA, whereas BPS is of comparable toxicity to BPA.

Modulated electro-hyperthermia in stage III and IV pancreatic cancer: Results of an observational study on 158 patients.

BACKGROUNDAn increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response.AIMTo compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer.METHODSThis was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups.RESULTSOverall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% (P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns.CONCLUSIONThe addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.

Arsenic Biotransformation: It is a complex process

Arsenic Biotransformation: It is a complex process

Preclinical Results of an Allogeneic, Universal CD19/CD7-Targeting CAR-T Cell Therapy (GC502) for B Cell Malignancies

BackgroundAutologous CD19 CAR-T therapies show very promising clinical efficacy, but are limited in their applicability by several factors including cost, time to manufacture, and other factors involving patients own T-cell qualities. GC027, a CD7 targeting allogeneic, universal CAR-T (UCAR-T) currently in development for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) has demonstrated robust expansion and anti-leukemia efficacy with a manageable safety profile in an investigator-initiated trial in China. These data suggest that, a single CD7 targeting CAR-T therapy is able to generate a therapeutic window by suppressing host vs graft (HvG) rejection of UCAR-T cells by patients' own NK and T cells, and achieve efficacy in patients with T-ALL. Based on these findings we developed GC502, a CD19/CD7 dual-targeting, allogeneic CAR-T therapy for B-cell malignancies, in which the CD19 CAR moiety targets malignant cells while CD7 CAR moiety suppresses HvG in variety of preclinical models.MethodsGC502 was manufactured using leukopaks from HLA-unmatched healthy donors. It contains a 4-1BB based 2 nd-generation dual targeting CAR comprising an anti-CD19 and an anti-CD7 single-chain variable fragments (scFvs). TRAC and CD7 loci were disrupted to avoid graft vs host disease and fratricide, respectively. To select the leading CAR candidate, CAR expression and functionalities of CAR constructs with different heavy-light (H-L) chain orientations of the dual CAR were analyzed via in vitro assays and mouse xenograft models, in comparing to single CD19 CAR and CD7 CAR products. To achieve optimal anti-tumor efficacy, a T-cell enhancer was included in the CAR construct.ResultGene editing and dual CAR orientation selectionTRAC and CD7 double knockout efficiencies were constantly above 97% across multiple donor pan T cells. Although CD19/CD7 CAR expression levels in different H-L chain orientations were similar, in the final CAR-T product as measured by flow cytometry (FCM) analysis, significant difference was observed in their cytotoxicity and in vitro expansion under repeated antigen stimulations by CD19+ B-cell acute lymphoblastic leukemia (B-ALL) cell line Nalm6 and CD7+ T-cell line CCRF-CEM. CAR candidates mediated the strongest cytotoxicity and most durable response were selected for further optimizations.CAR construct optimizationsFor the leading candidates, we first assessed the dual CAR efficacy after incorporation of an enhancer. While the IL-2, TNFα and IFNγ secretion levels were comparable, enhancer addition significantly improved tumor killing and CAR-T cell expansion under repeated stimulations by either CD19+ or CD7+ target cells. Anti-leukemia response under sub-optimal CAR-T cell dosages were also greatly enhanced as assessed by both B-ALL and T-ALL mouse xenograft models.GC502 CAR functionality comparison to single CAR products with proven clinical efficaciesGC502 and GC027 were compared for their CD7 CAR function to assess their anti-HvG activities. GC502 and GC027 exhibited comparable toxicities towards pan T cells and similar efficacies in a highly malignant T-ALL mouse model. The CD19 CAR functionality of GC502 were evaluated and compared to a 2 nd generation CD19 CAR product comprising a FMC63 scFv and a 4-1BB-CD3ȥ signaling domain. In a Raji based B-ALL mouse xenograft model, both products rapidly eliminated cancer cells. While CD19 CAR treated mice showed signs of relapse at 2 weeks post CAR-T infusion, GC502 treatment group maintained “leukemia free” status till the end of study (Day28).ConclusionGC502 was optimized for CD19/CD7 dual CAR functionality and in vivo durability. It demonstrated robust anti-tumor efficacy and promising potentials to suppress HvG. This report presents an example that the dual CAR design of GC502 may serve as a novel “off-the-shelf” CAR-T technology. DisclosuresGe: GracellBiotechnologies Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Sun: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Chen: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Qiu: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Yin: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Shen: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Sersch: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Cao: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Wang: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company.

A Comparison of Oncologic Outcomes and Toxicity with Combined Modality Therapy vs. Carbon Ion Radiotherapy for Locally Recurrent Rectal Cancer in Previously Irradiated Patients

<h3>Purpose/Objective(s)</h3> No standard treatment paradigm for previously irradiated, locally recurrent rectal cancer (LRRC) exists. We present comparative oncologic, toxicity, and cost data of previously irradiated patients with LRRC undergoing CIRT versus combined modality therapy (CMT). <h3>Materials/Methods</h3> Patients with LRRC treated between 2006 and 2019 with CIRT alone (n = 85, 70.4 Gy in 16 fractions) at institution A, or CMT (n = 86, photon external beam radiotherapy 30 Gy in 15 fractions with concurrent chemotherapy followed by resection and intraoperative radiotherapy) at institution B were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), and distant metastases (DM) were analyzed using the Kaplan-Meier method and competing risk model to report cumulative incidence. Treatment modality was compared using the Cox proportional hazards model. Acute and late toxicities, as well as a 2-year costs were compared. <h3>Results</h3> Median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 years and 2.6 years, respectively (HR 0.50 (0.33 – 0.76), <i>P</i> < 0.01). Two- and five-year OS were 83.1% (75.0 – 92.0) and 46.8% (35.2 – 62.3) for CIRT patients and 62.5% (52.5 – 74.4) and 25.7% (17.4 – 38.1) in CMT patients. The five-year cumulative incidence of PR was 53.6% (43.1 – 66.7) for CIRT patients and 36.7% (27.2 – 49.3) in CMT patients (HR 1.40 (0.87 – 2.27), <i>P</i> = 0.17). The five-year cumulative incidence of DM was 61.4% (51.2 – 73.5) for CIRT patients and 50.6% (40.4 – 63.2) in CMT patients (HR 1.20 (0.79 – 1.83), <i>P</i> = 0.39). Acute and late toxicities favored CIRT (Table 1). Costs (over a 2-year period) were higher for CMT than CIRT (median: $96,499 vs. $30,144). <h3>Conclusion</h3> Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT. OS was better with CIRT, potentially attributable to differences in baseline patient health, comorbidities; although, tumor biology cannot be excluded. Prospective comparative studies are needed.

Hypofractionated vs. Twice Daily Radiotherapy for Limited Stage Small-Cell Lung Cancer: A Propensity Score-Matched Analysis

<h3>Purpose/Objective(s)</h3> Concurrent twice-daily 45Gy radiotherapy (concurrent-BID) remains the standard treatment for limited stage small-cell lung cancer (LS-SCLC). However, this regime is inconvenient and not universally adopted across different institutions, therefore hypofractionated schedule is more and more investigated. The aim of this study was to compare concurrent -BID with sequential hypofractionated radiotherapy (sequential-Hypo) in LD-SCLC by propensity score-matched analysis. We hypothesize that sequential-Hypo could be used as an alternative without increased toxicities. <h3>Materials/Methods</h3> A retrospective analysis was conducted in 108 LS-SCLC patients treated between January 2015 and July 2019 in our institution. All patients received BID (45Gy/30F, n = 79, twice daily) or sequential-Hypo (54Gy/18F, n = 18; 45Gy/15F, n = 6; 60Gy/20F, n = 5, once daily) radiotherapy. After matching by propensity score, the survival, failure patterns and toxicities were compared. <h3>Results</h3> After propensity score matching, the confounders of patient characteristics between BID group (n = 24) and sequential-Hypo group (n = 24) were well balanced (age, <i>P</i> = 0.718; T staging, <i>P</i> = 0.149; N staging, <i>P</i> = 0.712; PCI, <i>P</i> = 0.755; performance status, <i>P</i> = 0.578). Before PSM, multivariate analysis showed that patients treated with sequential-Hypo had significantly better OS and DMFS (<i>P</i> = 0.009, HR = 0.353; <i>P</i> = 0.020, HR = 0.315, respectively). Total radiotherapy time≥24 days and stage III (<i>P</i> = 0.004, HR = 2.452; <i>P</i> = 0.055, HR = 2.310, respectively) were poor prognostic indicators for OS. Patients with T3 and T4 were more likely to recur than others (HR = 3.269, <i>P</i> = 0.040). N 2-3 and PS = 1 (<i>P</i> = 0.006, HR = 7.342; <i>P</i> = 0.023, HR = 10.384, respectively) were poor prognostic indicators for DMFS. After PSM by multivariable analyses, age≥65 years and total radiotherapy time≥24 days were associated with poorer OS (<i>P</i> = 0.004, HR = 4.222; <i>P</i> = 0.046, HR = 2.671, respectively). Although there was no significant difference, the patients in sequential-Hypo group had a trend to have a better OS. Before PSM, distant metastasis was the dominant failure pattern and was significantly less in sequential-Hypo group (17.7% vs 40.5%, <i>P</i> < 0.05). No significant difference was observed between BID group and Hypo group before and after PSM. <h3>Conclusion</h3> Sequential-Hypo schedule was associated with comparable survival and toxicity outcomes and may be considered as an alternative to concurrent-BID. Prospective trials are needed to confirm this result.

Comparative toxicity of conventional and unconventional oils during rainbow trout (Oncorhynchus mykiss) embryonic development: From molecular to health consequences

Canadian freshwater ecosystems are vulnerable to oil spills from pipelines, which contain mostly diluted bitumen. This study aimed to compare the toxicity of a dilbit and a conventional oil on developing rainbow trout. A total of five exposure scenarios were performed, from 10 to 43 days, using water-accommodated fraction (WAF) with an initial loading of 1:9 oil to water ratio (w/v) in a range of dilutions from 0.32 to 32% WAF, respectively, with TPAH and VOC concentrations from 2.41 to 17.5 μg/L and 7.94–660.99 μg/L, and with or without a recovery period. Following the five exposures, several endpoints were examined, including survivorship, morphometrics, gene expression, and enzymatic activity. Significant mortality rates were measured for the highest WAF concentration of the dilbit in all five exposures (60–100% mortality at 32% WAF). In comparison, the highest WAF concentration of the conventional oil induced significant mortality in three out of the five exposure (from 35 to 100% mortality at 32% WAF). Hatching delays were noted in embryos exposed to both oils. Developmental delays were observed in dilbit-exposed embryos and are suspected to be an indicator of reduced survivorship after hatching. The induced expression of cyp1a remained a reliable biomarker of exposure and of fish malformations, though it did not always predict mortality. Using CYP1A activity in combination with cyp1a may bring more insights in studies of oil risk assessment. This study demonstrates that dilbits are more toxic to early life stages compared to conventional oils and highlights the need to consider the most sensitive stage of development when performing risk assessment studies on oils.

Comparative developmental toxicity of conventional oils and diluted bitumen on early life stages of the rainbow trout (Oncorhynchus mykiss).

Petroleum hydrocarbons are widely used and transported, increasing the risks of spills to the environment. Although conventional oils are the most commonly produced, the production of unconventional oils (i.e. diluted bitumen or dilbit) is increasing. In this study, we compared the effects of conventional oils (Arabian Light and Lloydminster) and dilbits (Bluesky and Clearwater) on early life stages of a salmonid. To this end, aqueous fractions (WAF: water accommodated fraction) of these oils were extracted using mountain spring water. Rainbow trout (Oncorhynchus mykiss) larvae were exposed to 10 and 50% dilutions of these WAFs from hatching (340 DD; degree days) until yolk sac resorption (541 DD). Exposure to WAFs increased skeletal malformations (both dilbits) and hemorrhage (both conventional oils and Bluesky) and decreased head growth (Arabian Light). In addition, increases in EROD activity and DNA damage were measured for all oils and an increase in cyp1a gene expression was measured for Arabian Light, Bluesky and Clearwater. The PAH and C10C50 concentrations were positively correlated to total larval EROD activity, whereas concentrations of total hydrocarbons, VOCs, PAHs, and C10C50 were positively correlated to cyp1a expression. Total hydrocarbon, VOC, and C10C50 concentrations were also negatively correlated to larval growth. This study supports that petroleum hydrocarbons are toxic to early developmental stages of rainbow trout and show that their degree and spectrum of toxicity depends on their chemical composition.

P-186: Toxicity and survival outcomes of autologous stem cell transplant in Multiple Myeloma patients with renal impairment

<h3>Background</h3> High dose therapy followed by autologous stem cell transplant (ASCT) remains a standard of care for eligible patients with multiple myeloma(MM) as it has been shown to deepen responses and prolong progression-free survival (PFS). There is some evidence to support the use of ASCT in patients with renal impairment and is recommended by IMWG for the management of MM in renally impaired patients. Some of the studies however, have shown increased risks associated with ASCT, coupled with somewhat poorer outcomes in this group of patients. Through this multicentre retrospective study, we demonstrate the feasibility of ASCT in patients with renal impairment (creatinine clearance <60ml/min) and document the safety, PFS and overall survival (OS) of this cohort, in comparison to patients who did not have renal impairment immediately prior to ASCT (CrCl≥60ml/min). <h3>Methods</h3> Patients with MM who had renal impairment at diagnosis who underwent ASCT between 2010-2018 were identified from the institutional disease registries. They were then stratified into 2 groups – the first cohort had renal impairment at diagnosis and at ASCT while the second cohort had renal impairment at diagnosis but with normal renal function prior to ASCT. The patient characteristics, safety and survival outcomes were collected and the data was analysed using STATA. A total of 50 patients were identified, 38 patients had renal impairment and 12 patients had normal renal function prior to ASCT. There was no difference in the baseline characteristics between both groups, including age, sex, prognostic scores (ISS, R-ISS), first line induction therapy, best response to first line therapy and mean peripheral blood stem cells collected. <h3>Results</h3> There was increased incidence of grade 3 or 4 neutropenia during ASCT (100% vs 83.3%, p=0.00) in the cohort of patients with renal impairment. However, this did not translate to increased febrile neutropenia episodes (73.7% vs 91.7%, p=0.19), or prolonged admission (20.7 vs 22.7 days, p=0.97). The incidences of serious grade 3 or 4 adverse events such as anaemia, thrombocytopenia, diarrhoea and vomiting were not different between both cohorts. The dose of melphalan used for ASCT was attenuated in patients with renal impairment (133mg VS 197mg, p=0.02). Despite this difference, the mean number of days taken for neutrophil and platelet engraftment were similar (11.0 vs 12.1 days p=0.02 and 14.1 vs 13.1days, p=0.97 respectively). Overall outcomes also did not differ between patients with renal impairment vs normal renal function, with comparable 3-year PFS (60.5% VS 58.3%, p=0.849) and 3- year OS (78.9% VS 83.3%, p=0.86). <h3>Conclusion</h3> Taken together, our cohort of patients with renal impairment had comparable toxicity profiles and overall outcomes as compared to patients with normal renal function. As such, ASCT should be considered in patients who present with renal impairment in line with the international recommendations so as to optimise their long-term outcomes.