Toxicity Data Research Articles

LGG-18. BEVACIZUMAB: GOOD FOR EYES AND MRI’S! A NATIONAL UK ASSESSMENT OF VISUAL AND RADIOLOGICAL OUTCOMES OF BEVACIZUMAB THERAPY IN PAEDIATRIC LOW-GRADE GLIOMA (PLGG)

Abstract INTRODUCTION Bevacizumab (BEV) is increasingly used for PLGGs in varying manners despite limited evidence. The potential for BEV to preserve or rescue vision in OPGs has not yet been explored. We performed a nationwide UK evaluation of BEV use for PLGG to provide large cohort safety & efficacy (radiological & visual) data. METHODS A retrospective UK multi-centre analysis of patients treated with BEV for PLGG 2009-2020. Clinical patient, tumour, treatment and toxicity data were analysed from medical records. Age-adjusted LOGMAR visual acuity and radiological MRI assessments (RANO) were reviewed from initiation of BEV until latest follow-up. Standardized radiological & visual criteria assessed efficacy and clinical–radiological correlation. RESULTS 88 PLGG patients from 11 PTCs received BEV either 3rd-line with irinotecan (85%) or alongside 1st/2nd line chemotherapy (15%) at median age 6 years (0.65-17). Median duration from diagnosis to BEV was 38 months. PLGGs included:15% Non-OPGs, 85% OPGs. Cohort OS 92% at median follow-up 34 months(3-106). Toxicity was limited and minimal. 8% stopped BEV for CTCAE grade 2+ toxicities, & 3 patients had SAEs (2 intracranial haemorrhages, 1 thrombosis) after stopping BEV without obvious alternative cause. Overall radiological response (SD/PR/CR) was 88%; median duration to best response 3 months. Overall visual response (stable/improved) was 72%; median duration to best response 3-6 months. Superior visual outcomes were seen in NF1-OPGs (p=0.02). Concordance between visual and radiological responses was 36%; 48% using best eye only visual responses. 65% patients with treatment response had tumour progression (all-cause) within 8 months of BEV cessation. Visual responses endured significantly longer than radiological responses (p0.03). CONCLUSIONS BEV is a generally safe and effective treatment for PLGG. Most patients demonstrated on-treatment radiological and visual response. Preservation of response after BEV was limited, though visual responses endured better than radiological responses. BEV may have a unique role as a sight-saving strategy in OPG.

Assessment of potential environmental and human risks for Bisphenol AF contaminant

Bisphenol AF (BPAF) is found in high concentrations in aquatic environments due to the increased use of thermal paper and food packaging. However, there have been relatively few toxicological studies and potential risk assessments of BPAF. In this study, the risk quotient (RQ) and hazard quotient (HQ) of BPAF were derived to present the safety standards for environmental risk management and protection in lakes, rivers, bays, and Italian regions. We applied the species sensitivity distribution (SSD) method based on the previous ecotoxicological data and the results of supplementary toxicity tests on BPAF. From the SSD curves, the hazardous concentration for 5 % of the species (HC5) values for the acute and chronic toxicity data were 464.75 µg/L and 3.59 µg/L, respectively, and the acute- and chronic-based predicted no-effect concentration were derived as 154.92 µg/L and 1.20 µg/L, respectively. The acute-based RQ (RQA)values of BPAF in all regions were negligible (RQ < 0.1). The chronic-based RQ (RQC) in the Xitang River (XR) and the Central Italy (CI) showed a considerably high ecological risk (12.77 and 1.29) and the Hangzhou Bay (0.21), the South and North Italy (0.79 and 0.27), and the Tamagawa River (0.13) had a medium ecological risk (0.1 < RQ < 1.0). However, the HQ values based on the tolerable daily intake for BPAF over all age groups in these regions was < 0.1, indicating the low health risk. Nonetheless, the result of this study indicates that BPAF contamination is serious in XR and CI, and their use and emissions require continuous monitoring.

Potential impacts of titanium dioxide nanoparticles on the biochemical and behavioural status of the amphipods Talitrus saltator (Amphipoda, Talitridae)

ABSTRACT Titanium dioxide nanoparticles (TiO2 NPs) are among the most universally engineered nanomaterials and widely used nanomaterials in the world. In order to predict the environmental impact and interaction between these NPs and coastal organisms, the amphipod Talitrus saltator was exposed to TiO2 NPs C1 = 151.5 µg.L−1 and TiO2 NPs C2 = 303 µg.L−1. Catalase activity increased significantly and reaches a maximum of about 0.8 ± 0.02 µMol/min/mg proteins after exposure to TiO2 NPs C2 showing possible oxidative mechanisms. In addition, acetylcholinesterase activity reduced significantly (p < 0.05) after exposure to the highest TiO2 NPs concentration, indicating neurotransmission disturbance treated with 303 µg.L−1 of TiO2 NPs. Locomotor behaviour for untreated and treated specimens with TiO2 NPs was studied under constant darkness (DD). Results revealed the existence of ultradian and circadian components. In addition, locomotor activity patterns were generally bimodal for untreated specimens and became multimodal for treated ones. We noted also a slippage of the activity peak from the middle of the subjective night for the control until the subjective day after TiO2 NPs exposure. Furthermore, the most important stability was observed for control individuals who were more active than treated ones. Overall, this laboratory study provides preliminary toxicity data for Talitrus saltator exposed to TiO2 NPs.

Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants.

Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data. Over the past decade, an in vitro battery was developed to enhance DNT assessment, consisting of assays that evaluate cellular processes in neurodevelopment and function. In this study, behavioral data of small model organisms were also included. To assess if these assays provide sufficient mechanistic coverage to prioritize chemicals for further testing and/or identify hazards, an integrated approach to testing and assessment (IATA) was developed with additional information from the Integrated Chemical Environment (ICE) and the literature. Human biomonitoring and exposure data were identified and physiologically-based toxicokinetic models were applied to relate in vitro toxicity data to human exposure based on maximum plasma concentration. Eight OPFRs were evaluated, including aromatic OPFRs (triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP)) and halogenated FRs ((Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP)). Two representative brominated flame retardants (BFRs) (2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA)) with known DNT potential were selected for toxicity benchmarking. Data from the DNT battery indicate that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. However, these assays provide limited information on the mechanism of the compounds. By integrating information from ICE and the literature, endocrine disruption was identified as a potential mechanism. This IATA case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health.

LGG-55. DIFFERENTIAL TOXICITY PROFILE OF INDIVIDUAL MEK INHIBITORS: A MULTI-INSTITUTION RETROSPECTIVE REVIEW

Abstract BACKGROUND Most pediatric low-grade gliomas (pLGGs) are driven by molecular aberrations in the mitogen-activated protein kinase pathway (MAPK), which can be targeted by novel agents such as MEK inhibitors (MEKi.) However, MEKi use is accompanied by a varied side effect profile, with the most severe dose-limiting effects involving dermatologic, cardiac, and ophthalmic toxicities. METHODS Multi-institutional retrospective chart review of patients less than 25 years of age who underwent MEKi monotherapy between 2015-2022 was conducted. Data was collected from 4 sites, including Connecticut Children’s, St. Louis Children’s Hospital, Cardinal Glennon Children’s Hospital, and Children’s Hospital of Philadelphia. RESULTS Ninety-six patients were included in the analysis; 54 (56.4%) with brain tumors and 56 (58.3%) with germline mutation in NF-1. Forty-nine (51%) received trametinib, 42 (43.8%) selumetinib, 5 (5%) binimetinib. Of 42 patients with skin toxicity data available, 35 (83%) had cutaneous toxicity, with the most prevalent being acneiform rash (40.0%), followed by maculopapular rash (28.6%) and eczematous dermatitis (11.4%). The mean number of cutaneous skin toxicities was 2.4 (trametinib group = 2.2, selumetinib group = 2.6). Eighteen of 96 (18.8%) patients experienced cardiac toxicity, of which 11 (61.1%), experienced reduction in left ventricular ejection fraction (6 trametinib, 5 selumetinib), 4 (22.2%) developed pericardial effusions. 10 of 96 (10.4%) patients experienced ophthalmic toxicities, most commonly blurred vision (30.0%). Other toxicities included elevated CK (36, 37.5%), anemia (32, 33.3%), and eosinophilia (17, 17.7%). CONCLUSION There was not an observable clinically relevant difference in toxicities between MEKi, with skin toxicity the most prevalent. The prevalence of cardiac toxicity in the patient cohort reinforces the need for appropriate monitoring via echocardiography. MEKi remain an excellent option for therapy for LGG but with the need for continued supportive care and monitoring.

Validating self-reported Toxic Release Inventory data using Benford's Law: investigating toxic chemical release hazards in floodplains.

Acute and long-term health impacts from flooding related toxic chemical releases are a significant local health concern and can disproportionately impact communities with vulnerable populations; reliable release data are needed to quantify this hazard. In this paper, we analyze US Federal Emergency Management Agency designated floodplain data and US Environmental Protection Agency Toxic Release Inventory (TRI) data to determine if geographically manipulated databases adhere to Benford's Law. We investigated multiple variants and discovered pollution releases adhere to Benford's Law and tests which thereby validates the self-reported toxic release dataset. We find that Benford's Law applies to self-reported toxic chemical release and disposal data, indicating a lack of widespread data errors or manipulation.

REDOMA: Bayesian random-effects dose-optimization meta-analysis using spike-and-slab priors.

The rise of cutting-edge precision cancer treatments has led to a growing significance of the optimal biological dose (OBD) in modern oncology trials. These trials now prioritize the consideration of both toxicity and efficacy simultaneously when determining the most desirable dosage for treatment. Traditional approaches in early-phase oncology trials have conventionally relied on the assumption of a monotone relationship between treatment efficacy and dosage. However, this assumption may not hold valid for novel oncology therapies. In reality, the dose-efficacy curve of such treatments may reach a plateau at a specific dose, posing challenges for conventional methods in accurately identifying the OBD. Furthermore, achieving reliable identification of the OBD is typically not possible based on a single small-sample trial. With data from multiple phase I and phase I/II trials, we propose a novel Bayesian random-effects dose-optimization meta-analysis (REDOMA) approach to identify the OBD by synthesizing toxicity and efficacy data from each trial. The REDOMA method can address trials with heterogeneous characteristics. We adopt a curve-free approach based on a Gamma process prior to model the average dose-toxicity relationship. In addition, we utilize a Bayesian model selection framework that uses the spike-and-slab prior as an automatic variable selection technique to eliminate monotonic constraints on the dose-efficacy curve. The good performance of the REDOMA method is confirmed by extensive simulation studies.

Combined use of ecotoxicity tools and physicochemical analysis for evaluating potential toxicity of treated natural rubber processing effluents and receiving waters.

Potential toxicity of treated effluents of selected natural rubber processing industries was evaluated by integrating physicochemical analysis with Daphnia magna and Poecilia reticulata bioassays as ecotoxicity tools. Further, the efficacy of the constructed wetland treatments practiced by the industries for reducing the ecotoxicity of the final effluents reaching the receiving water course was assessed. Even after passing through the constructed wetlands, some of the measured physicochemical parameters of the final effluents did not comply with the stipulated rubber processing effluent regulatory limits. Acute toxicity data of treated effluents demonstrated greater susceptibility of D. magna compared to P. reticulata. Erythrocytic abnormality tests with P. reticulata revealed that rubber industry effluents contained cytogenotoxic contaminations which had not been completely eliminated by the treatment processes. Wetland treatment technique was not effective in reducing the cytogenotoxic effects of final effluents reaching the receiving water course. The use of ecotoxicity tools for optimization of rubber industry effluent treatment processes would help to reduce potential toxic/cytogenotoxic effects of effluent receiving waterbodies considering sustainable development goals focusing on ecosystem safety.

Temperate Versus Arctic: Unraveling the Effects of Temperature on Oil Toxicity in Gammarids.

Shipping activities are increasing with sea ice receding in the Arctic, leading to higher risks of accidents and oil spills. Because Arctic toxicity data are limited, oil spill risk assessments for the Arctic are challenging to conduct. In the present study, we tested if acute oil toxicity metrics obtained at temperate conditions reflect those at Arctic conditions. The effects of temperature (4 °C, 12 °C, and 20 °C) on the median lethal concentration (LC50) and the critical body residue (CBR) of the temperate invertebrate Gammarus locusta exposed to water accommodated fractions of a fuel oil were determined. Both toxicity metrics decreased with increasing temperature. In addition, data for the temperate G. locusta were compared to data obtained for Arctic Gammarus species at 4 °C. The LC50 for the Arctic Gammarus sp. was a factor of 3 higher than that for the temperate G. locusta at 4 °C, but its CBR was similar, although both the exposure time and concentration were extended to reach lethality. Probably, this was a result of the larger size and higher weight and total lipid content of Arctic gammarids compared to the temperate gammarids. Taken together, the present data support the use of temperate acute oil toxicity data as a basis for assessing risks in the Arctic region, provided that the effects of temperature on oil fate and functional traits (e.g., body size and lipid content) of test species are considered. As such, using the CBR as a toxicity metric is beneficial because it is independent of functional traits, despite its temperature dependency. To the best of our knowledge, the present study is the first to report CBRs for oil. Environ Toxicol Chem 2024;43:1627-1637. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Chemical hazard assessment toward safer electrolytes for lithium-ion batteries.

Commercialization of rechargeable lithium-ion (Li-ion) batteries has revolutionized the design of portable electronic devices and is facilitating the current transition to electric vehicles. The technological specifications of Li-ion batteries continue to evolve through the introduction of various high-risk liquid electrolyte chemicals, yet critical evaluation of the physical, environmental, and human health hazards of these substances is lacking. Using the GreenScreen for Safer Chemicals approach, we conducted a chemical hazard assessment (CHA) of 103 electrolyte chemicals categorized into seven chemical groups: salts, carbonates, esters, ethers, sulfoxides-sulfites-sulfones, overcharge protection additives, and flame-retardant additives. To minimize data gaps, we focused on six toxicity and hazard data sources, including three empirical and three nonempirical predictive data sources. Furthermore, we investigated the structural similarities among selected electrolyte chemicals using the ChemMine tool and the simplified molecular input line entry systeminputs from PubChem to evaluate whether chemicals with similar structures exhibit similar toxicity. The results demonstrate that salts, overcharge protection additives, and flame-retardant additives contain the most toxic components in the electrolyte solutions. Furthermore, carbonates, esters, and ethers account for most flammability hazards in Li-ion batteries. This study supports the complementary use of quantitative structure-activity relationship modelsto minimize data gaps and inconsistencies in CHA. Integr Environ Assess Manag 2024;20:2231-2244. © 2024 The Author(s). Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

The toxicity swimmer plot: A novel approach for evaluating patient-level toxicity following immune checkpoint inhibitor (ICI) therapy on the Checkmate 214 trial.

11014 Background: Treatment with ICIs creates the possibility of prolonged disease control or remission but also creates the possibility of prolonged toxicity even after treatment is discontinued. Treatment-free survival (TFS) with and without toxicity has previously been described as an integral piece of a partitioned survival analysis in advanced renal cell carcinoma (aRCC). Prior analyses have reported further partition of TFS as mean duration of TFS with and without treatment-related adverse events (TRAEs), but this metric fails to provide more granular information regarding individual patients experiencing toxicity during TFS. We present a novel extended swimmer plot that characterizes patient-level toxicity data within TFS using the example of the Checkmate 214 trial to complement analyses of the population average experience. Methods: Data were analyzed from the Checkmate 214 trial which randomized 1096 patients with aRCC to receive either first-line (1L) nivolumab plus ipilimumab (n = 550) or sunitinib (n = 546). The minimum follow-up from protocol therapy initiation was 42 months. Patients’ overall survival was partitioned into 3 survival states: time on 1L protocol therapy, TFS, and survival after subsequent therapy initiation. With a re-defined time origin relative to cessation of 1L protocol therapy, we generated swimmer plots highlighting the TFS period and documenting each patient’s experience with and without grade 2+ and grade 3+ TRAEs during TFS. The swimmer plot was sorted by duration of TFS and duration of TFS with grade 2+ TRAEs in order to illustrate patterns of individuals’ experiences. Results: The 42-month mean TFS was 7.8 months (with grade 2+ TRAEs: 3.2 months) for patients treated with nivolumab plus ipilimumab and 3.3 months (1.6 months) for patients treated with sunitinib. In the respective treatment groups, TFS with grade 2+ TRAEs was experienced by 32% and 25% of patients and comprised of 13% and 9% of patients for whom it was the entire TFS period. These percentages were consistent regardless of TFS duration. TFS with grade 3+ TRAEs was experienced by 15% and 3% of patients, respectively. For most patients having TFS with TRAEs, the TRAEs persisted from the protocol therapy period, but 7% and 1% of patients in the respective treatment groups had new-onset grade 3+ TRAE during TFS. A swimmer plot will be presented as a visual presentation of this study’s results. Conclusions: We describe a novel extension of swimmer plots for presenting patient-level information and illustrating patterns in toxicity duration relative to TFS by incorporating individual toxicity data into a swimmer plot of partitioned survival. This approach allows for a more comprehensive understanding of toxicity trends and risk of prolonged toxicity after treatment is discontinued.

Baseline PSMA PET/CT as a predictive biomarker for toxicity and patient-reported outcomes in mCRPC patients undergoing 177Lu-PSMA radioligand therapy.

e17058 Background: The phase III VISION trial demonstrated that 177Lu-PSMA-617 (PSMA-RLT) prolonged overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Common side effects of PSMA-RLT include xerostomia, bone pain, and myelosuppression. The objective of this study is to evaluate the role of baseline PSMA PET/CT (bPET) in predicting hematologic toxicity and patient-reported outcomes in mCRPC patients undergoing PSMA-RLT. Methods: Patients treated with 177Lu-PSMA-617 in the Expanded Access Program at UCLA with available bPET, toxicity data, and patient-reported outcomes (BPI, FACT-P, and Xerostomia Questionnaire) were included in this retrospective analysis. TRAQinform IQ technology (AIQ Solutions-Madison, WI) was used to conduct region of interest (ROI)-based analyses at bPET. SUVmean, SUVmax, volume (cm3), and total lesion PSMA (TLP; SUVmean x volume) of the whole-body tumor burden, healthy bone, and the salivary glands were extracted. We evaluated the following associations: 1) Whole-body tumor parameters on bPET with time to worsening of FACT-P scores (defined as a decrease of &gt;10 points from baseline) and time to first occurrence of Grade 3 or 4 hematologic toxicity (Multivariate Cox regression model); 2) Healthy bone parameters on bPET with time to worsening of BPI Pain Severity and Pain Interference scores (defined as a 30% increase or at least 2 points from baseline) and time to first occurrence of Grade 3 or 4 hematologic toxicity (Multivariate Cox regression model); 3) Salivary gland parameters on bPET with Xerostomia Questionnaire scores (Mixed-effect linear regression model). Results: 61 mCRPC patients were included. When evaluating associations between healthy bone SUVmean, SUVmax, and TLP with time to first occurrence of Grade 3 or 4 hematologic toxicity, baseline hemoglobin was associated with a longer time to first occurrence (HR = 0.61, p = 0.005; HR = 0.59, p = 0.002; HR = 0.62, p = 0.005 respectively). When evaluating associations between bPET and time to worsening of FACT-P scores, whole-body tumor SUVmean, SUVmax, and TLP were associated with a longer time to worsening (HR = 0.74, p = 0.033; HR = 0.82, p = 0.01; HR = 0.91, p = 0.028 respectively). When evaluating associations between salivary gland SUVmean, volume, SUVmax, and TLP with Xerostomia Questionnaire scores, the number of cycles was associated with higher scores (mean estimate: 0.63, p = 0.003; mean estimate: 0.64, p = 0.003; mean estimate: 0.64, p = 0.003; mean estimate: 0.63, p = 0.003 respectively). Conclusions: In this retrospective analysis of 61 mCRPC patients treated with PSMA-RLT, bPET parameters were generally not predictive of hematologic toxicity or patient-reported outcomes. Of note, whole-body tumor SUV was associated with a longer time to worsening of FACT-P scores. Validation in a larger, prospective cohort is warranted.

Adjuvant BRAF/MEK versus anti-PD-1 in BRAF-mutant melanoma: Propensity score–matched recurrence-free, distant metastasis-free, and overall survival analysis.

9573 Background: Adjuvant BRAF/MEK inhibitors (BRAF/MEKi) and immunotherapy with anti-PD-1 have become the standard of care for resected high-risk stage III and IV melanoma, but a head-to-head comparison is lacking. In our earlier study, we compared adjuvant BRAF/MEKi and anti-PD-1 in a nationwide cohort in the Netherlands. However, the follow-up was too limited for overall survival (OS) analysis. We present an updated analysis including OS with extended follow-up. Methods: We included all resected high-risk stage III melanoma patients treated with first-line adjuvant BRAF/MEKi and anti-PD-1 from the Dutch Melanoma Treatment Registry from 2018-2023. We performed a propensity score matched outcome analysis of 1- and 2-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and OS. Grade ≥ 3 toxicity rates and discontinuation rates due to toxicity were described. Results: In total, 225 BRAF/MEKi-treated patients and 729 anti-PD-1-treated patients were included. BRAF/MEKi-treated patients had lower disease stages (16.4% versus 10.2% stage IIIA disease; p=0.01) and more comorbidities (76.0% versus 63.8%; p&lt;0.01) than anti-PD-1-treated patients. Median follow-up duration was 20.9 months. Two similar groups of 213 patients each were created by propensity score matching. Before matching, RFS and DMFS were significantly shorter in the anti-PD-1 treated patients, OS was not (Table). After matching, the 1- and 2-year RFS, DMFS and OS rates were not significantly different (Table). Toxicity data will be presented at the meeting. Conclusions: Our results suggest no significant differences in outcomes between adjuvant BRAF/MEKi and anti-PD-1 treatment in stage III melanoma.[Table: see text]

Association of neighborhood-level superfund sites with atmospheric toxic exposures and increasing cancer risk in the United States: A proof-of-concept geospatial study.

10577 Background: Decades of underinvestment have disproportionately exposed several neighborhoods in the US to hazardous conditions. Superfund is the name given to the environmental program established by the US Congress in 1980, to address abandoned hazardous waste sites. The extent to which Superfund sites have contributed to differences in cancer risk remains unknown. We investigated atmospheric toxic exposures increasing cancer risk by proximity to Superfund sites at the neighborhood level. Methods: In this cross-sectional study of US neighborhoods, census-tract level air toxic cancer risk data from the Environmental Protection Agency for 2019 were linked with census-tract level geolocation data of ~1300 Superfund sites from the Superfund Enterprise Management System database. Linear regression models were utilized to explore association between cancer risk and proximity to Superfunds. Geographically Weighted Regression models explored spatial non-stationarity by modeling spatial relationships that vary across the study area. Bivariate Local Indicators of Spatial Association (LISA) cluster maps were created for superfund site proximity and cancer risk (high-high, low-low, low-high, high-low). Kruskal-Wallis testing compared the distributions of different variables across the four LISA cluster types. Results: Study explored 82,770 census tracts nationwide. For every 10 percentile increase in Superfund proximity, there was an increase of 4% in cancer risk (p &lt; 0.001). This association was strongest in the Intermountain West, South-Southeast, and Northeast regions. High-high clusters (high proximity to Superfund, high cancer risk) had higher percentage of non-White, low-income, unemployed and lower education attainment populations compared to low-low clusters (all p &lt; 0.001). Within high-high clusters, non-White population had the strongest correlation with proximity to Superfunds. Cancer risk was much higher for the top 10% than the bottom 10% of proximity to Superfunds (Table). Conclusions: Our study highlights higher clustering of cancer risk around neighborhoods with existing Superfund sites. Further, we demonstrate the closer a neighborhood is to a Superfund site, the greater the cancer risk is with associated sociodemographic changes. Using a novel approach to geospatial analytics, the results demonstrate the first clear evidence of a dangerous association between Superfunds and healthcare, and encourage the urgent prioritization of Congressional policies that optimize investment in Superfund site clean up for public health. [Table: see text]

Breast cancer outcomes and treatment toxicity in geriatric patients compared to other patients at the Cancer Disease Hospital in Zambia.

e13773 Background: Breast cancer is the second most common cancer in women in Zambia and the most common cancer in older women. Management of geriatric cancer patients can be challenging due to physiological changes and multiple comorbidities. Methods: Data was extracted from the CDH electronic database of breast cancer patients for November 2005 - November 2022. Geriatric patients were defined as those 65 years old or older. Data was analyzed using descriptive statistics. Clinical-pathologic characteristics and outcomes for geriatric (GP) and younger patients were compared using the Chi Squared Test/Fisher’s exact test for discrete and Student’s T-test for continuous variables. All p-values were two-sided. Results: Of 1981 patients, 493 (24.9%) were geriatric. 374 (18.9%) had Stage I/II cancer, 607 (30.6%) Stage III, 579 (29.2%) de novo Stage IV, with no differences between geriatric and younger patients. 441 (22.2%) had hormone receptor-positive (HR+) disease, 115 (5.8%) had HER2+ by IHC, 195 (9.3%) were triple-negative, 52 (2.6%) HR+HER2+. Geriatric patients were more likely to have invasive lobular carcinoma (4.6% v. 2.4%), less likely to have grade 3 (42.0% v 50.6%) or HER2+ (11.6% v 19.3%) cancer. 1889 (94.8%) received systemic treatment, 1188 (60.0%) surgery, and 844(42.6%) radiation (RT), with no differences in geriatric and younger patients. Geriatric patients were less likely to receive palliative RT (9.6% v 15.7%), to receive a lower total RT dose and had similar rates of RT dermatitis as younger patients. Geriatric patients were less likely to be treated with doxorubicin, docetaxel and more likely with methotrexate. After median follow-up of 1.1 years (st. dev 2.6), 301(15.2%) were alive without disease, 826 (41.7%) alive with cancer, 203 (10.2%) died from cancer, with no difference in local, distal recurrence, or survival for geriatric patients. Geriatric patients were less likely to be in good physical condition (33.9% v 39.4%) and more likely to have a worse ECOG (1.0% v 0.4% for ECOG 4, 4.1% v 2.4% for ECOG 3, 14.0% v 10.9% for ECOG 2, 73.4% v 75.8% for ECOG 1, 7.4% v 10.4% for ECOG 0). Geriatric patients had a lower number of total treatment toxicities (OR 0.95, 95% CI 0.91-0.98) and were less likely to have leukopenia (OR 0.89, 95% CI 0.83-0.94) and neutropenia (OR 0.88, 95% CI 0.82-0.95). (for similar outcomes p-value &gt; 0.05; all where differences are noted p-value &lt; 0.05). Conclusions: GPs were similar to other patients in terms of cancer stage and outcomes and had less aggressive disease. GPs had worse functional status, received less toxic chemotherapy, were less likely to receive surgery and RT. GPs had either a similar amount or less treatment toxicity compared to other patients. Results are limited by short follow-up of about 1.5 years. Results are limited by incomplete non-hematologic toxicity data.

Developing Kinetic and Organ Toxicity Data with a Novel In Vitro Human-Based Multiple Organ MPS: Acrylamide as a Case Study

Developing Kinetic and Organ Toxicity Data with a Novel <i>In Vitro</i> Human-Based Multiple Organ MPS: Acrylamide as a Case Study

Phase IB/II first line panitumumab, irinotecan, trifluridine/tipiracil in RAS wild-type patients with metastatic colorectal cancer: PIT study.

e15532 Background: Trifluridine/tipiracil (TT) is an oral fluoropyrimidine (FP) currently used in later line therapy. Preclinical data have demonstrated synergistic activity when panitumumab (Pmab) or irinotecan (Ir) are combined with TT supporting use in combination schedules in early line protocols. PIT was a phase IB/II study determining the maximum tolerated dose (MTD), safety and tolerability of substituting FP with TT, combined with Pmab and Ir in RAS wild-type mCRC. Methods: Phase IB 3+3 design dose escalation study (Dose level 1: TT 20mg/m2 oral BD, Ir 150mg/m2 IV, Pmab 6mg/m2). Primary objective was MTD of the combination in RAS WT mCRC patients, either 1st or 2nd line. Treatment was administered in 14-day cycles. Pmab and Ir were administered intravenously on day 1 with TT dosed orally, bid, days 1-5. Once MTD was established the phase II expansion study was to enrol 50 previously untreated mCRC patients. Primary endpoint was modified to toxicity. Results: The study closed due to slow recruitment. 14 patients were enrolled from 6/18 to 10/21. Med follow up 23 months. Med age 59 yrs (range 37-74yrs). 60% were male. One patient each was BRAF MT and right sided. ECOG 0/1 50%/50%. Thirteen patients had PIT as first line, 57% had prior adjuvant therapy. There was one DLT in first 3 patients however based on additional toxicity data (Clin Cancer Res. 2020 Apr 1:1555) a decision was made to not dose escalate beyond level 1 and commence phase II. Overall Gd 3 toxicity: Acne/rash 46%, Diarrhoea 31%, Fatigue 8%, neutropenia 15%, hypomagnesaemia 23%. One patient had Gd 4 neutropenia and there was one treatment related death (neutropenic sepsis). 12 patients had evaluable disease, 58% PR, 42% SD. Survival: Med PFS 14.1 mths, Med OS 40.6mths and 12 mth OS 64%. Conclusions: The MTD was deemed TT 20mg/m2, irinotecan 150mg/m2 and panitumumab 6mg/kg. Toxicity was manageable however significant grade 3 diarrhoea and rash was seen. There was one toxic death contributed to therapy. Small numbers do make interpretation difficult however there is a signal of activity. The slow recruitment illustrates difficulty in exploring novel combinations in early lines and potentially the reluctance to consider first line anti-EGFR therapy. Clinical trial information: ACTRN12617001190392.

Hepatotoxicity of silver nanoparticles: Benchmark concentration modeling of an in vitro transcriptomics study in human iPSC-derived hepatocytes

Despite two decades of research on silver nanoparticle (AgNP) toxicity, a safe threshold for exposure has not yet been established, albeit being critically needed for risk assessment and regulatory decision-making. Traditionally, a point-of-departure (PoD) value is derived from dose response of apical endpoints in animal studies using either the no-observed-adverse-effect level (NOAEL) approach, or benchmark dose (BMD) modeling. To develop new approach methodologies (NAMs) to inform human risk assessment of AgNPs, we conducted a concentration response modeling of the transcriptomic changes in hepatocytes derived from human induced pluripotent stem cells (iPSCs) after being exposed to a wide range concentration (0.01–25 μg/ml) of AgNPs for 24 h. A plausible transcriptomic PoD of 0.21 μg/ml was derived for a pathway related to the mode-of-action (MOA) of AgNPs, and a more conservative PoD of 0.10 μg/ml for a gene ontology (GO) term not apparently associated with the MOA of AgNPs. A reference dose (RfD) could be calculated from either of the PoDs as a safe threshold for AgNP exposure. The current study illustrates the usefulness of in vitro transcriptomic concentration response study using human cells as a NAM for toxicity study of chemicals that lack adequate toxicity data to inform human risk assessment.

Modeling Full Life-Cycle Effects of Copper on Brook Trout (Salvelinus fontinalis) Populations.

Population models are increasingly used to predict population-level effects of chemicals. For trout, most toxicity data are available on early-life stages, but this may cause population models to miss true population-level effects. We predicted population-level effects of copper (Cu) on a brook trout (Salvelinus fontinalis) population based on individual-level effects observed in either a life-cycle study or an early-life stage study. We assessed the effect of Cu on predicted trout densities (both total and different age classes) and the importance of accounting for effects on the full life cycle compared with only early-life stage effects. Additionally, uncertainty about the death mechanism and growth effects was evaluated by comparing the effect of different implementation methods: individual tolerance (IT) versus stochastic death (SD) and continuous versus temporary growth effects. For the life-cycle study, the same population-level no-observed-effect concentration (NOECpop) was predicted as the lowest reported individual-level NOEC (NOECind; 9.5 µg/L) using IT. For SD, the NOECpop was predicted to be lower than the NOECind for young-of-the-year and 1-year-old trout (3.4 µg/L), but similar for older trout (9.5 µg/L). The implementation method for growth effects did not affect the NOECpop of the life-cycle study. Simulations based solely on the early-life stage effects within the life-cycle study predicted unbounded NOECpop values (≥32.5 µg/L), that is, >3.4 times higher than the NOECpop based on all life-cycle effects. For the early-life stage study, the NOECpop for both IT and SD were predicted to be >2.6 times higher than the lowest reported NOECind. Overall, we demonstrate that effects on trout populations can be underestimated if predictions are solely based on toxicity data with early-life stages. Environ Toxicol Chem 2024;43:1662-1676. © 2024 SETAC.

Factors associated with acute esophagitis during radiation therapy for lung cancer

IntroductionLimiting acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC). MethodsDemographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012 to 2022 across a statewide consortium. Logistic regression models were used to characterize the risk of grade 2 + and 3 + esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50 % risk of grade 2 esophagitis and 3 % risk of grade 3 esophagitis. ResultsOf 1760 patients, 84.2 % had stage III disease and 85.3 % received concurrent chemotherapy. 79.2 % of patients had an ECOG performance status ≤ 1. Overall rates of acute grade 2 + and 3 + esophagitis were 48.4 % and 2.2 %, respectively. On multivariate analyses, performance status, mean esophageal dose (MED) and minimum dose to the 2 cc of esophagus receiving the highest dose (D2cc) were significantly associated with grade 2 + and 3 + esophagitis. Concurrent chemotherapy was associated with grade 2 + but not grade 3 + esophagitis. For all patients, MED of 29 Gy and D2cc of 61 Gy corresponded to a 3 % risk of acute grade 3 + esophagitis. For patients receiving chemotherapy, MED of 22 Gy and D2cc of 50 Gy corresponded to a 50 % risk of acute grade 2 + esophagitis. ConclusionsPerformance status, concurrent chemotherapy, MED and D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans.