Non-cancer Outcomes Research Articles

Mortality and cancer incidence in the UK glass reinforced plastics manufacturing industry: a cohort study

ObjectivesAccording to the International Agency for Research on Cancer, styrene is probably carcinogenic for lymphohaematopoietic neoplasms, with insufficient evidence for other cancer sites. We compared mortality and cancer incidence (for...

Human Plasma Proteomic Profile of Clonal Hematopoiesis.

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer novel insights into downstream clinical consequences. Here, we explore such patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 ancestrally diverse participants (3,881 with CHIP) from NHLBI TOPMed and UK Biobank with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2,917 proteins by Olink in UK Biobank), we identified 32 and 345 unique proteins from TOPMed and UK Biobank, respectively, associated with the most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations showed substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangled causal proteomic perturbations from TET2 CHIP. Lastly, we identified plasma proteins shared between CHIP and CAD.

A competing risks machine learning study of neutron dose, fractionation, age, and sex effects on mortality in 21,000 mice

This study explores the impact of densely-ionizing radiation on non-cancer and cancer diseases, focusing on dose, fractionation, age, and sex effects. Using historical mortality data from approximately 21,000 mice exposed to fission neutrons, we employed random survival forest (RSF), a powerful machine learning algorithm accommodating nonlinear dependencies and interactions, treating cancer and non-cancer outcomes as competing risks. Unlike traditional parametric models, RSF avoids strict assumptions and captures complex data relationships through decision tree ensembles. SHAP (SHapley Additive exPlanations) values and variable importance scores were employed for interpretation. The findings revealed clear dose–response trends, with cancer being the predominant cause of mortality. SHAP value dose–response shapes differed, showing saturation for cancer hazard at high doses (> 2 Gy) and a more linear pattern at lower doses. Non-cancer responses remained more linear throughout the entire dose range. There was a potential inverse dose rate effect for cancer, while the evidence for non-cancer was less conclusive. Sex and age effects were less pronounced. This investigation, utilizing machine learning, enhances our understanding of the patterns of non-cancer and cancer mortality induced by densely-ionizing radiations, emphasizing the importance of such approaches in radiation research, including space travel and radioprotection.

A Historical Survey of Key Epidemiological Studies of Ionizing Radiation Exposure.

In this article we review the history of key epidemiological studies of populations exposed to ionizing radiation. We highlight historical and recent findings regarding radiation-associated risks for incidence and mortality of cancer and non-cancer outcomes with emphasis on study design and methods of exposure assessment and dose estimation along with brief consideration of sources of bias for a few of the more important studies. We examine the findings from the epidemiological studies of the Japanese atomic bomb survivors, persons exposed to radiation for diagnostic or therapeutic purposes, those exposed to environmental sources including Chornobyl and other reactor accidents, and occupationally exposed cohorts. We also summarize results of pooled studies. These summaries are necessarily brief, but we provide references to more detailed information. We discuss possible future directions of study, to include assessment of susceptible populations, and possible new populations, data sources, study designs and methods of analysis.

Examining carcinogenic and noncarcinogenic health risks related to arsenic exposure in Ethiopia: A longitudinal study

BackgroundThe carcinogenic properties of arsenic make it one of the most hazardous chemicals globally. Nevertheless, the exact level of human exposure to arsenic and the associated risks of cancer and non-cancer effects through different pathways in Ethiopia are still uncertain. ObjectiveThe primary aim of this study was to evaluate the risk of both cancer and non-cancer outcomes among children and adults who have been exposed to arsenic through drinking water in the Adami Tulu Jido Kombolcha district of Ethiopia. MethodsFor this study, a longitudinal study design was employed. A total of 45 groundwater sources were sampled using the census sampling method. The concentrations of total arsenic were measured using Agilent 7900 series inductively coupled plasma mass spectrometry. Carcinogenic and noncarcinogenic risk assessments were conducted by calculating lifetime cancer risk and hazard quotients. Microsoft Office Excel was utilized to calculate human health risk indices, and descriptive statistical analysis were performed using SPSS software. ResultsOur findings revealed that during the dry season, the mean arsenic concentration in the groundwater samples was 11.15 ± 9.38 µg/L, while during the rainy season, it was 10.67 ± 8.16 µg/L. The total cancer risk for children, resulting from oral ingestion and skin contact, was 1.15 × 10–2 and 1.07 × 10–2 during the dry and rainy seasons, respectively. For adults, the total cancer risk from oral ingestion and skin contact during the dry and rainy seasons was 4.95 × 10–3 and 4.59 × 10–3, respectively. Furthermore, the total hazard quotients for children via oral ingestion and skin absorption were 25.9 and 24.0 during the dry and rainy seasons, respectively. For adults, the total hazard quotients from ingestion and dermal contact during the dry and rainy seasons were 11 and 10, respectively. ConclusionsThe findings indicate that the risks of cancer and non-cancer effects resulting from arsenic exposure through ingestion and dermal exposure were found to exceed the acceptable thresholds in both seasons. These results emphasize the urgent need for focused attention on the study population in the study area due to the high likelihood of experiencing adverse health outcomes.

Abstract B140: Towards cancer health justice: Considerations in designing a US cohort of 100,000 Black women

Abstract Background. Racism is a fundamental driver of health inequities, perpetuating systemic disadvantages that disproportionately impact marginalized communities. Structural racism affects multiple domains of an individual’s life, including housing, education, health, and employment. Recent studies have leveraged census data to examine the impact of racism—typically captured using area-level factors such as residential racial segregation and neighborhood socioeconomics—on health outcomes, including cancer. However, these studies often fail to capture the complex multidimensional mechanisms by which structural racism uniquely impacts minoritized groups and seldom consider facilitators of resilience, which may better inform interventions. Purpose. Large-scale contemporary cohort studies are needed to understand the drivers of social determinants of health and their potential impact on cancer. The American Cancer Society (ACS) has committed to establishing a US cohort of at least 100,000 Black women to understand multi-level drivers of cancer development and outcomes. Approach. ACS investigators have implemented a culturally sensitive approach that recognizes and validates the experiences of Black women, actively centering them in the design process. Relying on the principles of accountability, rigor, transparency, and impact to guide decision making, the research team has addressed novel challenges around eligibility, recruitment, and retention. ACS investigators considered the mechanisms and frequency of engagement to ensure meaningful participation. They designed survey tools to assess known drivers of cancer and non-cancer outcomes but reflect an understanding of the interconnected systems of oppression that uniquely impact marginalized communities. The research team has also taken steps to address expectations around the collection of biospecimens, recognizing the importance of establishing trust and respecting individual choice. Outcomes. The study population will be comprised of Black women between the ages of 25 and 55 years who reside in the District of Columbia or one of 20 US states. The ACS will partner with organizations primarily representing or serving the target population to identify interested participants. Study activities will be conducted through an online portal optimized for mobile use. Through the portal, interested individuals will complete an electronic eligibility survey, review the informed consent, and complete the 60-minute baseline survey. Follow-up questionnaires will be sent to participants twice per year for at least 30 years to track exposure and health outcomes and their lived experiences. Enrollment will take place in two pilot markets in Fall 2023 to test the feasibility of the recruitment, e-consent, and e-surveys with anticipated full-scale launch and biospecimen substudy in 2024. Conclusions. In designing a cohort of 100,000 Black women, ACS investigators aim to amplify the VOICES of Black women—honoring their lived experience and strengthening partnerships in the community for long-term health improvements. Citation Format: Lauren E. McCullough, Lauren R. Teras, Anusila Deka, Elizabeth G. Kirkland, Jeshondria McCray, Holly Vins, Jeuneviette E. Bontemps-Jones, Alpa V. Patel. Towards cancer health justice: Considerations in designing a US cohort of 100,000 Black women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B140.

Outcome of Atrial Fibrillation Ablation in Cancer Patients: A Review.

Atrial fibrillation (AF), a cardiac arrhythmia, exhibits a heightened prevalence among individuals diagnosed with cancer, notably prominent in cases of lung and gastrointestinal malignancies. Robust evidence from extensive studies underscores this association, emphasizing its clinical significance. However, the precise mechanistic underpinnings and specific risk factors linking cancer and AF remain a subject of incomplete understanding. Notably, the prevalence of AF in cancer patients substantially exceeds that in non-cancer counterparts, prompting further exploration of the underlying pathophysiological processes. This review aims to address the existing knowledge void regarding AF management in cancer patients, with a specific focus on the potential role of ablation procedures. While catheter and surgical ablation techniques have been thoroughly investigated and validated as effective treatments within non-cancer populations, their applicability and outcomes in cancer patients have remained inadequately explored. The principal objective of this exhaustive review is to bridge this research gap by conducting a meticulous examination of the feasibility, safety, and effectiveness of ablation interventions for AF in the context of cancer patients. By amalgamating existing evidence and pinpointing critical areas necessitating additional investigation, this review endeavors to provide invaluable insights into AF management in cancer patients, with the ultimate goal of enhancing their clinical care and optimizing outcomes.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a “safe” or “no-risk” level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Deep Breaths: A Systematic Review of the Potential Effects of Employment in the Nuclear Industry on Mortality from Non-Malignant Respiratory Disease.

Ionizing radiation is an established carcinogen, but its effects on non-malignant respiratory disease (NMRD) are less clear. Cohorts exposed to multiple risk factors including radiation and toxic dusts conflate these relationships, and there is a need for clarity in previous findings. This systematic review was conducted to survey the body of existing evidence for radiation effects on NMRD in global nuclear worker cohorts. A PubMed search was conducted for studies with terms relating to radiation or uranium and noncancer respiratory outcomes. Papers were limited to the most recent report within a single cohort published between January 2000 and December 2020. Publication quality was assessed based upon UNSCEAR 2017 criteria. In total, 31 papers were reviewed. Studies included 29 retrospective cohorts, one prospective cohort, and one longitudinal cohort primarily comprising White men from the U.S., Canada and Western Europe. Ten studies contained subpopulations of uranium miners or millers. Papers reported standardized mortality ratio (SMR) analyses, regression analyses, or both. Neither SMR nor regression analyses consistently showed a relationship between radiation exposure and NMRD. A meta-analysis of excess relative risks (ERRs) for NMRD did not present evidence for a dose-response (overall ERR/Sv: 0.07; 95% CI: -0.07, 0.21), and results for more specific outcomes were inconsistent. Significantly elevated SMRs for NMRD overall were observed in two studies among the subpopulation of uranium miners and millers (combined n = 4229; SMR 1.42-1.43), indicating this association may be limited to mining and milling populations and may not extend to other nuclear workers. A quality review showed limited capacity of 17 out of 31 studies conducted to provide evidence for a causal relationship between radiation and NMRD; the higher-quality studies showed no consistent relationship. All elevated NMRD SMRs were among mining and milling cohorts, indicating different exposure profiles between mining and non-mining cohorts; future pooled cohorts should adjust for mining exposures or address mining cohorts separately.

Mortality and cancer incidence 1952–2017 in United Kingdom participants in the United Kingdom’s atmospheric nuclear weapon tests and experimental programmes

This study examines the mortality and cancer incidence experience among men who took part in the United Kingdom’s atmospheric nuclear weapon tests between 1952–67. A cohort of 21 357 servicemen and male civilians from the UK who participated in the tests and a group of 22 312 controls were followed between 1952 and 2017. Analyses of mortality and cancer incidence were conducted. The overall mortality rate in the test participants was slightly higher relative risk (RR = 1.02, 90% CI 1.00–1.05, p = 0.04) than that in the control group. This difference was driven by similar increased risks for both all cancers combined (RR 1.03, 90% CI 1.00–1.07) and all non-cancer diseases (RR = 1.02, 90% CI 1.00–1.05). Leukaemia excluding chronic lymphatic incidence showed evidence of being raised relative to controls (RR = 1.38, 90% CI 1.10–1.75, p = 0.01). Leukaemia risks were driven by increased risks for chronic myeloid leukaemia (CML) (RR = 2.43, 90% CI 1.43–4.13, p = 0.003). Among non-cancer outcomes only cerebrovascular diseases showed increases in participants relative to controls. UK nuclear weapon tests participants have lower mortality rates compared to the national population although rates are slightly (2%) higher than in the study control group. Variation in background characteristics, that could not be accounted for in the analysis (e.g. smoking habits, diet), are a possible explanation for this difference. For leukaemia evidence of increased risk in the early years after the test has generally continued to diminish with time although for CML risks have persisted. There was some evidence that participants had higher mortality rates from cerebrovascular diseases than those in the control group. Assuming recorded radiation exposures (generally very low) are a true reflection of actual exposures then it is unlikely that any observed health effect will have been caused by radiation exposure.

Heavy metal pollution of soils and risk assessment in Houston, Texas following Hurricane Harvey

In August 2017, after Hurricane Harvey made landfall, almost 52 inches of rain fell during a three-day period along the Gulf Coast Region of Texas, including Harris County, where Houston is located. Harris County was heavily impacted with over 177,000 homes and buildings (approximately 12 percent of all buildings in the county) experiencing flooding. The objective of this study was to measure 13 heavy metals in soil in residential areas and to assess cancer and non-cancer risk for children and adults after floodwaters receded. Between September and November 2017, we collected 174 surface soil samples in 10 communities, which were classified as “High Environmental Impact” or “Low Environmental Impact” communities, based on a composite metric of six environmental parameters. A second campaign was conducted between May 2019 and July 2019 when additional 204 soil samples were collected. Concentrations of metals at both sampling campaigns were higher in High Environmental Impact communities than in Low Environmental Impact communities and there was little change in metal levels between the two sampling periods. The Pollution Indices of lead (Pb), zinc, copper, nickel, and manganese in High Environmental Impact communities were significantly higher than those in Low Environmental Impact communities. Further, cancer risk estimates in three communities for arsenic through soil ingestion were greater than 1 in 1,000,000. Although average soil Pb was lower than the benchmark of the United States Environmental Protection Agency, the hazard indices for non-cancer outcomes in three communities, mostly attributed to Pb, were greater than 1. Health risk estimates for children living in these communities were greater than those for adults.

Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank study

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Study participants were 318,749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006–2010), and re-measured in 12,334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. After correction for multiple testing (P < 0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration = 1.12, 95% CI 1.08–1.16), and inversely associated with varicose veins (0.90, 0.85–0.95), cataracts (0.97, 0.95–0.99), diabetes (0.92, 0.90–0.95), and iron deficiency anaemia (0.90, 0.86–0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.

Immediate risk of non-cancer deaths after a cancer diagnosis

BackgroundReceiving a cancer diagnosis may trigger immediate fatal non-cancer health outcomes in addition to dying of cancer itself. We aim to investigate the full pattern of non-cancer deaths in patients within a year of a cancer diagnosis.MethodsPatients diagnosed with cancer between 1990 and 2016 were identified from the SEER program. Standardized mortality ratios (SMRs) were calculated to characterize the relative risks of non-cancer deaths compared with the general population.ResultsAmong 7,366,229 patients, 241,575 non-cancer deaths (15.9%) were recorded in the first year following a cancer diagnosis. The relative risk of non-cancer deaths was 2.34-fold (95% confidence interval (CI): 2.33–2.35) that of the general population. The majority of non-cancer deaths were caused by cardiovascular diseases (21.8%), followed by infectious diseases (7.2%). Significant elevations in mortality risks were observed for nearly all non-cancer causes, particularly in infectious diseases (SMR: 5.08; 95% CI: 5.03–5.13). Patients with liver cancer (SMR: 12.29; 95% CI: 12.06–12.53) were at the highest risk of early non-cancer deaths. The risks of non-cancer deaths were highest within the first month after diagnosis, and decreased rapidly thereafter.ConclusionsRisks of non-cancer deaths vary by the types of causes and anatomic sites of cancer. Our data underscore the importance of close observation and early multidisciplinary care for noncancer conditions in patients who have recently received a cancer diagnosis.

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

Background:Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.Objectives:We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.Methods:Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose–response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized.Results:We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose–response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose–response analysis.Conclusion:Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381

Using personal monitoring data to derive organ doses for medical radiation workers in the Million Person Study—considerations regarding NCRP Commentary no. 30

The study of low dose and low-dose rate exposure is of central importance in understanding the possible range of health effects from prolonged exposures to radiation. The One Million Person Study of Radiation Workers and Veterans (MPS) of low-dose health effects was designed to evaluate radiation risks among healthy American workers and veterans. The MPS is evaluating low-dose and dose-rate effects, intakes of radioactive elements, cancer and non-cancer outcomes, as well as differences in risks between women and men. Medical radiation workers make up a large group of individuals occupationally exposed to low doses of radiation from external x-ray/gamma exposures. For the MPS, about 100 000 United States medical radiation workers have been selected for study. The approach to the complex dosimetry circumstances for such workers over three to four decades of occupation were initially and broadly described in National Council on Radiation Protection and Measurements (NCRP) Report No. 178. NCRP Commentary No. 30 provides more detail and describes an optimum approach for using personal monitoring data to estimate lung and other organ doses applicable to the cohort and provides specific precautions/considerations applicable to the dosimetry of medical radiation worker organ doses for use in epidemiologic studies. The use of protective aprons creates dosimetric complexity. It is recommended that dose values from dosimeters worn over a protective apron be reduced by a factor of 20 for estimating mean organ doses to tissues located in the torso and that 15% of the marrow should be assumed to remain unshielded for exposure scenarios when aprons are worn. Conversion coefficients relating personal dose equivalent, H p(10) in mSv, to mean absorbed doses to organs and tissues, D T in mGy, for females and males for six exposure scenarios have been determined and presented for use in the MPS. This Memorandum summarises several key points in NCRP Commentary No. 30.

The life cycle approach for assessing the impact of municipal solid waste incineration on the environment and on human health

The impact of municipal solid waste incineration (MSWI) on the environment and on human health was assessed by a life cycle assessment (LCA) approach. Even if risk assessment and epidemiologic analyses are specifically indicated for the investigation of the health outcomes, they resulted costly, time intensive and generally focused only on the effects caused by pollutant compounds directly emitted by the facility. Differently, LCA approaches are less time and cost intensive and able to account also for other indirect and direct emission of MSWI. However, results returned by LCA are based on average pollutant diffusion and individual exposure models limiting their representativeness for the specific context investigated. Furthermore, LCA is not able to return information about the final health outcomes caused by the pollutants emitted. The LCA performed for the Italian MSWI detected avoided impacts of about −0.11 kgPM2,5eq/tonne of MSW and of about −2.5 × 10−3 kgSbeq/tonne MSW for particulate matters and resource depletion, respectively. Positive impacts of about 900 kgCO2eq/tonne MSW and about 15,000 CTUe/tonne MSW were detected for global warming and freshwater ecotoxicity indicators, respectively. Avoided impacts of about −1 × 10−6 CTUh/tonne MSW and of about −2 × 10−4 DALY/tonne MSW were also detected for human toxicity cancer and human health indicators, respectively. Epidemiologic studies referred to different Italian and EU reported some correlations among MSWI and some specific cancer and non-cancer health outcomes. By the way, these resulted affected by some methodological limitation preventing the definitive identification of causal nexus. In any case, a general coherence between LCA and epidemiologic approaches was detected. Furthermore, a particular correspondence was found between LCA results and biomonitoring studies concerning the concentration of heavy metals in blood and urinary samples of exposed individuals. All this highlighted the important role that LCA can have in supporting health impact assessment of MSWI in combination with epidemiologic approaches.

Protocol: mixed-methods study of how implementation of US state medical cannabis laws affects treatment of chronic non-cancer pain and adverse opioid outcomes

BackgroundThirty-three US states and Washington, D.C., have enacted medical cannabis laws allowing patients with chronic non-cancer pain to use cannabis, when recommended by a physician, to manage their condition. However, clinical guidelines do not recommend cannabis for treatment of chronic non-cancer pain due to limited and mixed evidence of effectiveness. How state medical cannabis laws affect delivery of evidence-based treatment for chronic non-cancer pain is unclear. These laws could lead to substitution of cannabis in place of clinical guideline-discordant opioid prescribing, reducing risk of opioid use disorder and overdose. Conversely, state medical cannabis laws could lead to substitution of cannabis in place of guideline-concordant treatments such as topical analgesics or physical therapy. This protocol describes a mixed-methods study examining the implementation and effects of state medical cannabis laws on treatment of chronic non-cancer pain. A key contribution of the study is the examination of how variation in state medical cannabis laws’ policy implementation rules affects receipt of chronic non-cancer pain treatments.MethodsThe study uses a concurrent-embedded design. The primary quantitative component of the study employs a difference-in-differences design using a policy trial emulation approach. Quantitative analyses will evaluate state medical cannabis laws’ effects on treatment for chronic non-cancer pain as well as on receipt of treatment for opioid use disorder, opioid overdose, cannabis use disorder, and cannabis poisoning among people with chronic non-cancer pain. Secondary qualitative and survey methods will be used to characterize implementation of state medical cannabis laws through interviews with state leaders and representative surveys of physicians who treat, and patients who experience, chronic non-cancer pain in states with medical cannabis laws.DiscussionThis study will examine the effects of medical cannabis laws on patients’ receipt of guideline-concordant non-opioid, non-cannabis treatments for chronic non-cancer pain and generate new evidence on the effects of state medical cannabis laws on adverse opioid outcomes. Results will inform the dynamic policy environment in which numerous states consider, enact, and/or amend medical cannabis laws each year.

Heavy metals in soils and edible tissues of Lepidium meyenii (maca) and health risk assessment in areas influenced by mining activity in the Central region of Peru.

Heavy metal contamination of soil and agricultural products is an environmental problem, has an adverse effect on the quality of food crops, and is a danger to food security and public health. The concentration of arsenic (As), cadmium (Cd), lead (Pb), iron (Fe) and zinc (Zn) in surface soils and edible hypocotyls tissues of two ecotypes of Lepidium meyenii Walpers (maca) was evaluated in three districts of the Junín province, Peru. In addition, the risk to human health due to exposure to heavy metals from maca consumption was evaluated. Soil samples and maca hypocotyls were collected in areas influenced by mining and metallurgical activity. The mean concentration of Cd (0.32 ± 0.23 mg/kg) and Pb (0.20 ± 0.12 mg/kg) in maca samples exceeded the values established by the Food and Agriculture Organization and the World Health Organization. The bioconcentration factor was less than 1. The estimated daily intake of each metal was below the oral reference dose. The hazard quotient and hazard index were less than 1, it is unlikely to cause non-cancer adverse health outcome. The cancer risk for As and Cd was higher than the tolerable limit (1 × 10-6) in children and adults. In the district of Ondores, the cancer risk for As in children was higher than the acceptable limit (1 × 10-4). Residents of the Ondores district would be more exposed to As and Cd from consumption of maca hypocotyls. It is very important to carry out continuous monitoring of other toxic metals in different ecotypes of maca (red, black, yellow, purple, creamy white, pink) in order to evaluate the variation in the accumulation of heavy metals and the level of toxicity of each metal between ecotypes.

Thromboxane metabolite excretion is associated with serious vascular events in diabetes mellitus: a sub-study of the ASCEND trial

Abstract Background Platelet activation plays a major role in the atherothrombotic complications of diabetes. Thromboxane (TX)A2 is a pro-thrombotic prostanoid, synthesized via cyclooxygenase-1 and released by activated platelets. The metabolism of TXA2 in vivo leads to a major stable end-product, 11-dehydro-TXB2 (TXM), measurable in urine and reflecting the whole-body rate of TXA2 biosynthesis. In two large trials of high-risk, aspirin-treated (mostly, without diabetes) patients, (CHARISMA and HOPE trials), the baseline rate of urinary TXM excretion was an independent predictor of future cardiovascular events. Purpose The aim of the ASCEND (A Study of Cardiovascular Events in Diabetes) TXM sub-study was to investigate the association between baseline urinary TXM and future serious vascular events or revascularization (SVE-R), major bleeds and incident cancer independent of other risk factors and treatment, in people with diabetes and no manifest cardiovascular disease at trial entry. Methods Urinary TXM was measured by a previously GC/MS-validated, immunoassay in 6,487 participants with eligible baseline samples. Analyses excluded 539 participants using NSAIDs. TXM appeared log-normally distributed, so analyses were by quintiles and per SD (=0.622) of continuous loge TXM. The association of loge TXM with outcome was adjusted by basic factors (age, sex, sample volume and randomized treatment allocation) and by the predictors of log TXM (smoking, type 2 diabetes treated with insulin or oral hypoglycaemics, HDL cholesterol, body mass index, urinary albumin/creatinine ratio, eGFR). The association of log TXM with non-vascular, non-cancer MedDRA outcomes was investigated to determine whether TXM had a general effect on outcome. During a mean of 6.6 years follow-up there were 618 SVE-Rs, 206 bleeds and 700 cancers among these patients. Results Log TXM correlated significantly with SVE-R, hazard ratio (HR) per 1 SD of log TXM: 1.13 (1.04–1.23), p=0.003 (Figure 1, panel a), non-significantly with major bleeds [HR 1.15 (1.00–1.32), p=0.055] (Figure 1, panel b), and marginally significantly with cancer [HR 1.09 (1.01–1.17), p=0.03] (Figure 1, panel c). There was no association of log TXM with non-vascular non-cancer MedDRA outcomes (HR per 1 SD, 0.99; 99% CI, 0.94–1.05). Conclusion The rate of urinary TXM excretion, a non-invasive biomarker of TXA2-mediated platelet activation in vivo, is log-linearly associated with serious vascular events independent of other risk factors in people with diabetes. Its potential association with cancer must be viewed as hypothesis-generating and needs confirmation. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): IMI1: Surrogate markers for micro- and macro-vascular hard endpoints for innovative diabetes tools (SUMMIT).

Aortic Strain -Threshold Analysis of Non-Cancer Outcome from Arsenic Exposure

Background: While arsenic has been shown in many studies to behave as a threshold carcinogen, analyses of non-cancer outcomes (e.g., cardiovascular) have generally been presented only using linear models. Alternative models have received little consideration. We choose here to examine aortic strain data, a known risk factor for hypertension and cardiovascular disease, on arsenic-exposed workers with alternative analytic modeling.Method: A previously published study (Karakulak et al., 2016) of aortic strain measurements in arsenic-exposed workers had demonstrated that aortic strain was markedly reduced among workers with high levels of arsenic exposure (urinary arsenic in ug/L). The original analysis was limited to a linear model without model validation. We have analyzed the data using alternative models.Results: Examination of the linear analysis and its residuals demonstrated significant heteroscedascity with unequal variances, particularly at urinary levels of &gt; 160 ug arsenic per liter (ug/L). The test of equal variances from samples with &gt;160 and samples &lt;= 160 demonstrated inequality (p &lt; 0.0001). The better alternative model was a step-function with a mean aortic strain of 11.3% for those with urinary arsenic &lt;= 160 ug/L and with a mean aortic strain of 5.3% for those with urinary arsenic &gt; 160 ug/L. A further stratified analysis with bins of 40 ug/L showed no effect on aortic strain for the urinary arsenic range of &lt;= 160 ug/L and, separately, no effect for the urinary arsenic range of &gt; 160 ug/L.Conclusion: Aortic elasticity parameters show an adverse effect from arsenic exposure only at urinary exposure levels of &gt; 160 ug/L and not below, indicating a step-function rather than a linear function. Restriction of analyses to a linear no-threshold model may have blinded the finding of a more useful demonstration of a dose-response pattern that may offer different toxicological interpretations.