Carcinogen Exposure Research Articles

Immediate Switching to Reduced Nicotine Cigarettes in a U.S.-Based Sample: The Impact on Cannabis Use and Related Variables at 20 Weeks.

The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated. This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups. CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20). Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes. The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).

Editors' Selections from Relevant Scientific Publications

Editors' Selections from Relevant Scientific Publications

S256 Risk Factors of Colorectal Cancer in Africa: A Systematic Review and Meta-Analysis

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. A recent meta-analysis estimated a pooled CRC age-standardized incidence rate of 5.25 per 100,000, though suggested this to be an under-estimate of the true rate. Due to the heterogeneity of dietary and lifestyle practices throughout the continent, our work sought to define risk factors for the development of CRC in Africa. Methods: We systematically searched PubMed, Embase, Global Health, CINAHL, Cochrane CENTRAL, and African Index Medicus for studies written in English, examining risk factors of CRC in Africa. Meta-analysis was performed to compare different risk factors in constituent studies. Jamovi software was used for statistical analysis utilizing a random-effects model. Analysis of CRC studies was supplemented by estimated relative risk (RR) comparing various risk factors. Results: Of 2479 studies screened, 149 were included for the quantitative analysis (n=93707). Family history of CRC was associated with a RR of 2.14 and 95% RR CI [1.68-2.72], n=340. Individuals with diets based on high calcium, or vegetable consumption had 45% and 8% lower chances of having CRC, with respective RR of 0.55 [0.44-0.69] and 0.92 [0.84-0.99]. Diets based on carbohydrate, dairy, sugary food/drinks, or meat consumption indicated 14, 31, 43, or 45% higher chances of CRC, and 1.14 [1.03-1.26], 1.31 [1.21-1.42], 1.43 [1.32-1.57], 1.45 [1.36-1.54], n=5303. Physical activity was associated with lower RR of having CRC (81% less), 0.19 [0.15-.26]. Individuals that were obese, have been exposed to carcinogenic chemicals, have history of alcohol use, or tobacco use indicated 43, 45, 54, 65% higher chance of CRC, with 1.43 [1.02-2.03], 1.45 [1.23-1.68], 1.54 [1.28-1.84], 1.65 [1.45-1.9], n=8995. With the exception of family history, there was considerable heterogeneity among studies (I2 > 80%). (Figure) Conclusion: There are both modifiable and non-modifiable risk factors that are distinct to Africa and vary across the continent. Our review revealed that obesity, carcinogen exposure, tobacco or alcohol use, and diets high in carbohydrates, dairy, and red meat increase CRC risk. On the contrary, high calcium or vegeTable-based diets, and physical activity are protective against the development of CRC. Further work is needed to characterize CRC risk factors by region and to understand the impact of risk factor mitigation efforts on the overall incidence of CRC.Figure 1.: Family history (panel a), type of diet (panel b), and type of lifestyle (panel c) risk factors of CRC in Africa, log relative-risk by case-control studies comparison

283 (PB063) - Replication protein A targeted therapy: In vivo anticancer activity and cellular target engagement

Background: Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure.

94P CD44v6: A potential therapeutic target for liver carcinoma

Liver cancer has a poor prognosis predominantly resulting from tumour heterogeneity and limited treatment options. The two predominant types of liver cancer are Hepatocellular carcinoma (HCC) and Intrahepatic Cholangiocarcinoma (iCCA). CD44v6, a splice variant of the hyaluronic acid receptor CD44, is a marker for cancer stem cells, and is known to impact tumour formation and metastasis in several cancers. The expression of CD44v6 dramatically increases in liver epithelial cells upon carcinogen exposure.

Serum Raman spectroscopy in experimental carcinogenesis hamster buccal pouch model: Exploring early diagnostic capability

AbstractAbout two third of oral cancer cases present at advanced stages, emphasizing the need for screening tools for early diagnosis. Raman spectroscopy (RS) can prove an appropriate tool for early diagnosis as biochemical changes occur before morphological changes. Due to limitations with study of early oral cancer stages in human subjects, we performed a sequential carcinogenesis study in animal model. In the present study, we aim to probe early biochemical changes occurring during DMBA induced oral carcinogenesis in hamster buccal pouch model, using serum RS (SRS). Serum being systemic biofluid can reflect the true in vivo state, is minimally invasive and offers advantages of remote diagnosis and serial sampling. The female Syrian golden hamsters were treated with 0.5% DMBA and retro‐orbital blood collection was performed every week for a period of 14 weeks. An increase in classification efficiency as the DMBA treatment progressed, with distinct classification of &gt;70% seen as early as week 5 (W5), appreciably early to development of visual changes (W8–W10) was observed. Furthermore, the early treatment weeks (W1–W4) and healthy condition (W0) show no misclassifications with weeks exhibiting frank tumours (W9–W14), demonstrating efficacy of SRS to stratify healthy versus carcinogen exposure. The findings suggest that as oral carcinogenesis progresses, biochemical alterations in serum such as increasing protein and loss of lipid content can be detected by RS, highlighting the feasibility and utility of SRS in early oral cancer diagnosis. To our knowledge, this is the first study exploring the ex vivo sequential approach to gain insights into oral cancer progression.

Quantifying sociodemographic inequities in exposure to point source carcinogenic industrial pollution emissions across the United States

Background/Aim: Few studies have investigated how carcinogenic environmental exposures are distributed among the general population. We described recent cross-sectional relationships between carcinogenic industrial emissions and sociodemographic characteristics across the United States (US). Methods: We linked US Environmental Protection Agency’s 2018 Toxics Release Inventory to sociodemographic characteristics in 2010 Census tracts. Using chemical abstract service registry numbers, we identified onsite emissions (e.g., air, landfill, surface) of known and probable carcinogens as classified by the International Agency for Research on Cancer. Tract characteristics included total population, median household income, Yost neighborhood deprivation index, poverty, and percentages of Black, Hispanic, and white populations. We used linear regression to investigate the relation between quintiles of emissions in each census tract and distributions of these characteristics. Results: 5,209 (7%) tracts with an estimated 23.2 million population contained 7,028 facilities emitting known (n=22) or probable (n=33) carcinogens, including 1 billion pounds of these emissions in total (median: 226; IQR 7-5970 pounds/tract). Compared to tracts without emissions (all p-values &amp;#x3c;0.01), those with the highest quintile of emissions had higher proportions of rural (44% vs. 19%) and white (71% vs. 62%) populations, lower median household income ($45,000 vs. $55,000), and a higher deprivation score (62 vs. 49). Tracts with the highest emissions had a higher proportion of population with a high school education or less (53% vs. 44%). Overall, the proportions of families below the poverty level did not differ; however, greater numbers of black and white families below poverty lived in the tracts with the highest emissions. We observed similar demographic patterns in analyses restricted to air emissions. Conclusions: Our novel assessment demonstrates that carcinogenic emissions are not homogeneously distributed among the US population. It may be important to consider joint distributions of sociodemographic characteristics when describing environmental exposures and associated health disparities. Keywords: carcinogens, health disparities

Rapid bioanalytical screening for the assessment of internalized exposure to Polycyclic Aromatic Hydrocarbons in clinical samples of Florida Firefighters

BACKGROUND AND AIM: Polycyclic aromatic hydrocarbons (PAHs) are toxic byproducts of combustion and ubiquitous environmental pollutants which can cause carcinogenesis. Firefighters are routinely exposed to these contaminants and numerous studies have described a high incidence of various cancer types in firefighters compared to the general population. Our aim was to develop a streamlined process that allows accurate quantitative evaluation of PAH exposure in clinical samples collected from Florida Firefighters. METHODS: Urine samples were collected from twenty-five (25) active firefighters stationed in Florida at the beginning and end of a 24-hour shift, and twenty-one (21) new recruits after the completion of different fire trainings. We developed a rapid, non-invasive method to assess their internalized exposure to PAHs as part of the Firefighter Cancer Initiative (FCI). The use of automated extraction systems and Gas Chromatography – Mass Spectrometry enabled the accurate, qualitative, and quantitative detection of PAHs identified as priority pollutants by the United States Environmental Protection Agency. RESULTS: Total PAH exposure levels of the 25 active firefighters were significantly higher after the completion of the 24-hour shift, with those that answered fire-related calls, rather than EMS calls, exhibiting the highest concentrations of individual and gross PAHs. Similarly, total internalized exposure was increased in firefighter trainees compared to controls. We observed that participation in a Class B fire training, which involves flammable liquid materials, is associated with higher exposure to PAHs compared to participation in Class A exercises that employ ordinary combustible materials. CONCLUSIONS: Our findings showcase the unsafe levels of carcinogen exposure faced routinely by firefighters, highlighting the need for further investigation of the link between occupational exposure and health-related effects. The novel biomonitoring tool we developed facilitates large-scale screening of clinical samples and can be used for real-time assessment of carcinogen exposure. KEYWORDS: PAHs, exposure assessment, firefighters, biomonitoring, occupational exposure

EP16.03-015 Centrosome Amplification Is a Prognostic Indicator and Potential Therapeutic Vulnerability in Non-small Cell Lung Cancer

Centrosomes are organelles that facilitate chromosome segregation. The number of centrosomes in a cell is tightly regulated to ensure the genome is divided equally during cell division. In normal cells, two centrosomes form a bipolar mitotic spindle for faithful chromosome segregation. Cancers often exhibit centrosome amplification (CA), an increase in centrosome number that can be caused by cellular insults such as cell cycle defects and carcinogen exposure. Cells with CA are prone to forming abnormal, multi-polar mitotic spindles which can induce aneuploidies that promote tumour progression.

Disease burden, risk factors, and trends of primary central nervous system (CNS) cancer: A global study of registries data.

This study aimed to evaluate the global incidence, mortality, associated risk factors, and temporal trends of central nervous system (CNS) cancer by sex, age, and country. We extracted incidence and mortality of CNS cancer from the GLOBOCAN (2020), Cancer Incidence in Five Continents series I-X, WHO mortality database, the Nordic Cancer Registries, and the Surveillance, Epidemiology, and End Results Program. We searched the Global Health data exchanges for the prevalence of its associated risk factors. We tested the trends by Average Annual Percentage Change (AAPC) from Joinpoint regression analysis with 95% confidence intervals in different age groups. The age-standardized rates (ASRs) of CNS cancer incidence and mortality were 3.5 and 2.8 per 100,000 globally. Southern Europe (ASR = 6.0) and Western Asia (ASR = 4.2) had the highest incidence and mortality, respectively. The incidence was associated with Human Development Index, Gross Domestics Products per capita, prevalence of traumatic brain injuries, occupational carcinogens exposure, and mobile phone use at the country level. There was an overall stable and mixed trend in the CNS cancer burden. However, increasing incidence was observed in younger male population from five countries, with Slovakia (AAPC = 5.40; 95% CI 1.88, 9.04; P = .007) reporting the largest increase. While the overall global trends of cancer have been largely stable, significant increasing trends were found in the younger male population. The presence of some higher-HDI countries with increasing mortality suggested an ample scope for further research and exploration of the reasons behind these epidemiological trends.

Spotlights: e-Cigarettes and Carcinogen Exposure, a New RAMP Risk Management Course, Rasputin’s Cyanide Poisoning Survival, and Shoring Up after an Earthquake

ADVERTISEMENT RETURN TO ARTICLES ASAPPREVSpotlightsNEXTSpotlights: e-Cigarettes and Carcinogen Exposure, a New RAMP Risk Management Course, Rasputin’s Cyanide Poisoning Survival, and Shoring Up after an EarthquakeLauren Goulding*Lauren Goulding*Email: [email protected]More by Lauren Goulding and Jessica A. MartinJessica A. MartinMore by Jessica A. Martinhttps://orcid.org/0000-0002-4083-0848Cite this: ACS Chem. Health Saf. 2022, XXXX, XXX, XXX-XXXPublication Date (Web):August 24, 2022Publication History Received12 August 2022Published online24 August 2022https://doi.org/10.1021/acs.chas.2c00062Published 2022 by American Chemical SocietyRIGHTS & PERMISSIONSArticle Views212Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (726 KB) Get e-AlertsSUBJECTS:Biomarkers,Inorganic carbon compounds,Safety,Sulfur,Toxicology Get e-Alerts

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1‐heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary‐specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR‐Cas9–based genome editing. Homozygotes (Brca1 L63X/L63X) were embryonic lethal, whereas heterozygotes (Brca1 L63X/+) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild‐type (WT) littermates during their lifetime. Intraperitoneal injection of 1‐methyl‐1‐nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1–2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose‐dependent mammary carcinogenesis with 0.8 Gy−1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1 L63X/+ rats thus offer the first single‐mutation, heterozygous model of BRCA1‐associated breast cancer, especially with exposure to a DNA break‐inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high‐risk BRCA1 mutations.

Oral Field Cancerization: A Review with Case Reports

The concept of field cancerization was proposed by Slaughter et al. in 1953. Field cancerization of the mucosa of aerodigestive tract frequently develops on account of tobacco and alcohol usage. The oral cavity is one of the predominant and prevalent sites of development of potential malignancies, therefore, it comes into direct contact with many carcinogens. All of the epithelium beyond the boundaries of tumour can undergo histological changes and may have more than one independent area of malignancy. The mucosa undergoes a change, perhaps due to carcinogen exposure and is therefore more susceptible to the development of many foci of malignant transformation. This explains the high incidence of recurrence of oral cancer, the rate being 32.7%, despite excision of tumour or other therapies. So, diagnosis and treatment of oral cancer should not only be focused on the lesion, but also on the field from which it developed. In this article, we emphasize on the concept of field cancerization, highlight the carcinogenic influence of tobacco and alcohol in the development of multiple primary tumours in the oral cavity by presenting clinical cases. Keywords: Field cancerization; Squamous cell carcinoma; Metastasis; Second primary tumours; Synchronous/ Metachronous tumours3.

Non-carcinogenic and Carcinogenic Health Risk Evaluation from Fish Contaminated with Heavy Metals

The pollution of water bodies with heavy metals can result into the possible contamination of freshwater fish. The levels of the heavy metals Pb, Fe, Cu, Zn, Ni and Cd were investigated in fish samples (Ameiurus nebulosus, Pylidictis olivaris, Tilapia zilli, Clarias gariepinus) collected from Kwanar-Are dam located at Rimi local government area Katsina State, Nigeria and the health risks of the evaluated heavy metals were estimated. The mean concentration ranges of Pb, Fe, Cu, Zn and Cd were (0.0851-0.4919, 0.3095-0.5039, 0.0366-0.0589, 0.1066-0.3015, 0.1048-0.1417, 0.0128-0.0686 mg/kg) respectively. The risk assessment for non-carcinogenic exposure effect showed that there was no health risk associated with these elements through consumption of the fish samples to the consumer population. However the risk assessment for carcinogenic exposure effect has revealed that the incremental lifetime cancer risk (ILCR) and the cumulative lifetime cancer risks (∑ILCR) were all above the safe limit for cancer in the children and the adults population for all the fish samples evaluated. The heavy metal Ni presented the greatest cancer risk and the fish sample Clarias gariepinus having the highest cancer risk. There is a degree of concern for consumption of the fish samples for their potentials to contribute to the population cancer risk load.

Development of Climate Health and Oncology-Based Curricula: Understanding Climate Change's Impact on Cancer Care and a Physicians' Role

<h3>Background</h3> Climate change has well-documented impacts across the cancer care continuum, from increased carcinogenic exposures to disruption of health care systems required for cancer prevention, screening, diagnosis, treatment, and follow-up care. Incorporating the impact of climate change into oncology training will be essential for future physicians. When surveyed, only 13% of U.S. medical students felt they were receiving adequate climate change and health (CCH) education. Yet there is no standard climate curriculum in medical education in part due to an abundance of essential topics that must be covered. In collaboration with a Climate Health Resources Education (CRHE) pilot, we present the development of climate health and oncology educational resources aimed at providing succinct, accessible, and evidence-based resources for educators to incorporate CCH into medical curricula. <h3>Methods</h3> In partnership with CRHE, oncology topics with associated evidence-based learning objectives were established. Recruitment of content creators took place via email distribution lists, professional societies (e.g., Healthcare Without Harm, Medical Students for a Sustainable Future), social media (i.e. Twitter), and word of mouth. Working groups with medical students, residents/fellows, faculty advisors, and an expert advisor were established. Using standardized CRHE templates, medical students wrote and designed practice-based learning cases, while residents created associated PowerPoint slide decks. Faculty mentors and expert advisors were responsible for content review and ensuring accuracy. <h3>Results</h3> For the oncology lectures, a collaborative working group of eight healthcare professionals was formed (4 medical students, 4 residents/fellows, 3 faculty advisors, and 1 expert advisor). Over the course of four weeks, two lectures with associated practice-based problems and slides were developed on the topics of, 1) particulate matter pollution and lung cancer; 2) climate change impacts across the cancer control continuum. The oncology CCH educational resources were incorporated into CRHE's topic-based longitudinal curriculum and will be made publicly available for online, open-access distribution across health training programs nationwide. <h3>Discussion</h3> It is essential for physicians-in-training to be educated on the topics of CCH, the impact on cancer control, and the effect on our communities. Future physicians will need to be prepared to adopt and advocate for climate-smart, sustainable, and resilient care to meet the shifting needs of a vulnerable population affected by a changing climate. This initiative exemplifies the collaborative effort that will be required to integrate climate health topics into medical education, including oncology-specific topics. We look forward to reporting further results on the adoption and implementation of the curriculum.

Scoping Review of 5 Common Occupational Cancers and Their Related Exposures.

Background: Occupational cancers can be avoided by removing dangerous chemicals from the workplace or limiting occupational exposure. Approximately, 10 major risk factors account for 85% of all occupational cancers. This scoping review study aimed to determine the most important chemical carcinogens related to 5 known occupational cancers. Methods: In this scoping review, we followed Arksey and O’Malley’s 5-step framework. Four databases (PubMed, Web of Science, Google Scholar, Scopus) were systematically reviewed for relevant published papers from January 2000 to September 2021. Studies were included in this scoping review, which examined the effect of carcinogenic (definite and probable) chemical exposures on 5 known occupational cancers (lung, bladder, laryngeal, leukemia, and liver). We reported the types of occupational carcinogens, the geographical diversity of studies, extraction of relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs), and identified gaps in the existing literature. Results: The highest number of studies was related to lung cancer (LC) (n = 26), bladder cancer (BC) (n = 11), laryngeal cancer (LaC) (n = 8), leukemia (LeC) (n = 3), and primary liver cancer (PLC) (n = 2), respectively. Most studies were performed in France and Canada (n = 8), Germany (n = 4), Finland (n = 3), Netherlands (n = 2), and Finland (n = 2), respectively. Furthermore, the most common occupational chemical carcinogens associated with the 5 known occupational cancers were asbestos, benzene, crystalline silica, polycyclic aromatic hydrocarbons (PAH), and diesel motor exhausts (DME). Conclusion: Although the attributable risk of occupational cancers in developing countries is much higher, a small proportion of studies were performed in these countries.

Development and therapeutic manipulation of the head and neck cancer tumor environment to improve clinical outcomes.

The clinical response to cancer therapies involves the complex interplay between the systemic, tumoral, and stromal immune response as well as the direct impact of treatments on cancer cells. Each individual's immunological and cancer histories are different, and their carcinogen exposures may differ. This means that even though two patients with oral tumors may carry an identical mutation in TP53, they are likely to have different pre-existing immune responses to their tumors. These differences may arise due to their distinct accessory mutations, genetic backgrounds, and may relate to clinical factors including previous chemotherapy exposure and concurrent medical comorbidities. In isolation, their cancer cells may respond similarly to cancer therapy, but due to their baseline variability in pre-existing immune responses, patients can have different responses to identical therapies. In this review we discuss how the immune environment of tumors develops, the critical immune cell populations in advanced cancers, and how immune interventions can manipulate the immune environment of patients with pre-malignancies or advanced cancers to improve therapeutic outcomes.

Inhalation Bioaccessibility and Risk Assessment of Metals in PM2.5 Based on a Multiple-Path Particle Dosimetry Model in the Smelting District of Northeast China.

PM2.5 can deposit and partially dissolve in the pulmonary region. In order to be consistent with the reality of the pulmonary region and avoid overestimating the inhalation human health risk, the bioaccessibility of PM2.5 heavy metals and the deposition fraction (DF) urgently needs to be considered. This paper simulates the bioaccessibility of PM2.5 heavy metals in acidic intracellular and neutral extracellular deposition environments by simulating lung fluid. The multipath particle dosimetry model was used to simulate DF of PM2.5. According to the exposure assessment method of the U.S. Environmental Protection Agency, the inhalation exposure dose threshold was calculated, and the human health risk with different inhalation exposure doses was compared. The bioaccessibility of heavy metals is 12.1–36.2%. The total DF of PM2.5 in adults was higher than that in children, and children were higher than adults in the pulmonary region, and gradually decreased with age. The inhalation exposure dose threshold is 0.04–14.2 mg·kg−1·day−1 for the non-carcinogenic exposure dose and 0.007–0.043 mg·kg−1·day−1 for the carcinogenic exposure dose. Cd and Pb in PM2.5 in the study area have a non-carcinogenic risk to human health (hazard index < 1), and Cd has no or a potential carcinogenic risk to human health. A revised inhalation health risk assessment may avoid overestimation.

Evaluating Real World Mutational Differences Between Hispanics and Asians in NSCLC at a Large Academic Institution in Los Angeles

IntroductionHispanics living in the United States have higher rates of Epidermal Growth Factor Receptor (EGFR) mutations compared with Non-Hispanic Whites. While this higher incidence is like Asian patients living in the United States, the outcomes for Hispanic patients differ. We looked to compare the variances in mutational profiles between Hispanics and Asians in Los Angeles. Patients and MethodsThree hundred ninety three non-small cell lung cancer (NSCLC) patients treated at Los Angeles County + University of Southern California (LAC + USC) Medical Center and Norris Comprehensive Cancer Center who received comprehensive genomic profiling (CGP) were evaluated from July 2017 to August 2020. CGP was done using tissue biopsies (n = 211) from Caris Life Sciences and liquid biopsies (n = 231) from Guardant Health. Multivariate logistic regression evaluated the role of race between Hispanics and Asians. ResultsIn the Hispanic cohort (n = 90), 50.0% were male, median age of diagnosis was 62, 54.5% were non-smokers, and 85.5% had adenocarcinoma. In Asians (n = 142), 47.5% were male, median age of diagnosis was 65, 59.6% were non-smokers, and 83.8% had adenocarcinoma. Hispanic patients had greater prevalence of Kirsten rat sarcoma virus (KRAS) mutations (odds ratio [OR] 4.42, 95% confidence interval [95% CI]: 1.63-12.83) and lesser prevalence of EGFR mutations (OR 0.31, 95% CI: 0.16-0.59). There were a greater proportion of Hispanic smokers with KRAS mutations (14/41; 34.1%) than Asian smokers (4/58; 6.9%). ConclusionWe saw a greater percentage of Hispanics with KRAS mutations despite similar smoking percentages along with a greater percentage of Asians with EGFR mutations. This study shows that ethnic and racial backgrounds of the patient can influence the effects of potentially carcinogenic exposures leading to variances of mutation frequency of NSCLC among different ethnicities.

Abstract 808: In vivo targeting of replication protein A for cancer therapy

Abstract Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second generation RPA inhibitors (RPAi’s) that block the RPA-DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first generation RPAi’s, second generation molecules with increased cellular permeability, induce cell death via apoptosis. Second gen RPAi’s elicit single agent in vitro anticancer activity across a broad spectrum of cancers and the cellular response supports a threshold exists before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors as well as traditional DNA damaging cancer therapeutics. Consistent with the chemical RPA exhaustion model, we demonstrate that the effects of RPAi on replication fork dynamics. An optimized formulation was developed that resulted in single agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAi’s eliciting a state of chemical RPA exhaustion can provide an effective therapeutic option for difficult to treat lung cancers. Citation Format: Pamela VanderVere-Carozza, Navnath Gavande, Shadia Jalal, Karen Pollok, Elmira Ekinci, Joshua Heyza, Steve Patrick, Andi Masters, John Turchi, Katherine Pawelczak. In vivo targeting of replication protein A for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 808.