Framing diagnostic error: an epidemiological perspective.

Diagnostic errors burden the United States healthcare system. Depending on how they are defined, between 40,000 and 4 million cases occur annually. Despite this striking statistic, and the potential benefits epidemiological approaches offer in identifying risk factors for sub-optimal diagnoses, diagnostic error remains an underprioritized epidemiolocal research topic.

Interventional probability of causation (IPoC) with epidemiological and partial mechanistic evidence: benzene vs. formaldehyde and acute myeloid leukemia (AML).

Introduction: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias.

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types. A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.

Lost in the woods: Finding our way back to the scientific method in systematic review.

Systematic review has become the preferred approach to addressing causality and informing regulatory and other decision-making processes, including chemical risk assessments. While advocates of systematic reviews acknowledge that they hold great potential for increasing objectivity and transparency in assessments of chemicals and human health risks, standardizing and harmonizing systematic review methods have been challenging. This review provides a brief summary of the development of systematic review methods and some of the frameworks currently in use in the US and Europe.

Systematic review of the scientific evidence of the pulmonary carcinogenicity of talc.

We conducted a systematic review to assess the potential pulmonary carcinogenicity of inhaled talc in humans. Our systematic review methods adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and incorporated aspects from the US Institute of Medicine (IOM) and several United States (US) Environmental Protection Agency (EPA) frameworks for systematic reviews. A comprehensive literature search was conducted.

Carcinogenicity of Poorly Soluble Low Toxicity Particles: Commentary on Epidemiology as a Risk Assessment "Reality Check".

Inhaled particles that are poorly soluble or insoluble and of low toxicity ("poorly soluble low toxicity" or "PSLT" particles), can accumulate in the lung and at lung overload levels induce lung cancers in rats. The question of whether PSLT particles increase lung cancer risk in humans is complicated by large differences between rats and humans and the relatively large particle doses administered in animal studies even when compared with heavy human occupational exposures. We review the findings of epidemiological studies on occupational exposure to each of three different PSLT particles (carbon black, talc and taconite).

Cross-sectional Study of Workers Employed at a Copper Smelter-Effects of Long-term Exposures to Copper on Lung Function and Chronic Inflammation.

Objective: The aim of the study was to assess the effect of exposure to copper-containing dust on lung function and inflammatory endpoints among workers of a German copper plant, effects rarely studied before.

Methods: One hundred four copper-exposed smelter workers and 70 referent workers from the precious metal and lead facilities were included, with different metal exposures in both groups due to the different process materials. Body plethysmography, exhaled nitric oxide (FeNO) measurements, and blood sampling were conducted in all workers.

Systematic review of the scientific evidence on ethylene oxide as a human carcinogen.

Ethylene oxide is a highly reactive chemical primarily used as an intermediate in chemical production and as a sterilant of medical equipment and food products; it also is produced endogenously as a result of physiological processes. We conducted a systematic review of the potential carcinogenicity of inhaled ethylene oxide in humans using methods that adhere to PRIMSA guidelines and that incorporate aspects from the Institute of Medicine (IOM) (now the National Academy of Medicine) as well as several US Environmental Protection Agency (EPA) frameworks for systematic reviews. After a comprehensive literature search and selection process, study quality was evaluated following a method adapted from the EPA Toxic Substances Control Act (TSCA) framework.

Underground salt and potash workers exposed to nitrogen oxides and diesel exhaust: assessment of specific effect biomarkers.

Purpose: Occupational exposure limits (OEL) for nitrogen oxides (NO, NO) and diesel exhaust (EC-DPM) were reassessed by the German authorities in 2016/2017. We performed a clinical cross-sectional study among salt and potash underground workers exposed to these substances at relatively high levels to examine possible indicators of acute effects on workers' health.

Methods: We measured post- versus pre-shift differences in cardiovascular, inflammatory, immune, and respiratory effect biomarkers and assessed their associations with personal exposures measured during the same shift.

A Health Surveillance Study of Workers Employed at a Copper Smelter-Effects of Long-Term Exposure to Copper on Lung Function Using Spirometric Data.

Objective: Significantly lower permissible occupational exposure limits for copper dust are being discussed in Europe and other jurisdictions. However, little data are published on exposures in occupational settings and copper-specific effects in humans. Hence, a health surveillance study was performed among workers employed at a copper smelter between 1972 and 2018.

Integration of Evidence on Community Cancer Risks from Elongate Mineral Particles in Silver Bay, Minnesota.

The potential for cancer-related risks to community members from ambient exposure to elongate mineral particles (EMPs) in taconite processing has not been formally evaluated. We evaluated 926 ambient air samples including 12,928 EMPs (particle structures with length-to-width ratio ≥3:1) collected over 26 years near a taconite processing facility in Silver Bay, Minnesota. Eighty-two percent of EMPs were ≤3 μm in length and 97% of EMPs had an average aspect ratio <20:1.

Occupational exposure to formaldehyde and risk of non hodgkin lymphoma: a meta-analysis.

Background: Formaldehyde, a widely used chemical, is considered a human carcinogen. We report the results of a meta-analyses of studies on the relationship between occupational exposure to formaldehyde and risk of non-Hodgkin lymphoma (NHL).

Methods: We performed a systematic review and meta-analysis according to international guidelines and we identified 12 reports of occupational populations exposed to formaldehyde.

Ethylene Oxide: Cancer Evidence Integration and Dose-Response Implications.

The International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (USEPA) classified ethylene oxide (EtO) as a known human carcinogen. Critically, both noted that the epidemiological evidence based on lymphoid and breast cancers was "limited," but that the evidence in animal studies was "sufficient" and "extensive" (respectively) and that EtO is genotoxic. The USEPA derived one of the highest published inhalation unit risk (IUR) values (3 × 10 per [µg/m EtO]), based on results from 2 epidemiological studies.

Extended Analysis and Evidence Integration of Chloroprene as a Human Carcinogen.

β-Chloroprene is used in the production of polychloroprene, a synthetic rubber. In 2010, Environmental Protection Agency (EPA) published the Integrated Risk Information System "Toxicological Review of Chloroprene," concluding that chloroprene was "likely to be carcinogenic to humans." This was based on findings from a 1998 National Toxicology Program (NTP) study showing multiple tumors within and across animal species; results from occupational epidemiological studies; a proposed mutagenic mode of action; and structural similarities with 1,3-butadiene and vinyl chloride.

Considerations for refining the risk assessment process for formaldehyde: Results from an interdisciplinary workshop.

Anticipating the need to evaluate and integrate scientific evidence to inform new risk assessments or to update existing risk assessments, the Formaldehyde Panel of the American Chemistry Council (ACC), in collaboration with the University of North Carolina, convened a workshop: "Understanding Potential Human Health Cancer Risk - From Data Integration to Risk Evaluation" in October 2017. Twenty-four (24) invited-experts participated with expertise in epidemiology, toxicology, science integration and risk evaluation. Including members of the organizing committee, there were 29 participants.

Peak Exposures in Epidemiologic Studies and Cancer Risks: Considerations for Regulatory Risk Assessment.

We review approaches for characterizing "peak" exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose-response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. We searched the epidemiologic literature on environmental chemicals classified as carcinogens in which cancer risks were described in relation to "peak" exposures.

The epidemiologic evidence for elongate mineral particle (EMP)-related human cancer risk.

Epidemiologic research on the role of fibers and other elongate mineral particles (EMP) and human diseases including cancers has generated a large body of literature over the last decades: nevertheless, there remain some questions for which the scientific community appears unable to reach consensus. Reasons for genuine differences in opinion include (i) ways in which exposures have been classified; (ii) methodological limitations of the available studies, (iii) criteria for the interpretation of study results, including potential underlying biological mechanisms, and (iv) methodology for integrating the evidence. Various approaches have been proposed in recent years to address these issues, which will be illustrated using examples from asbestos, talc, taconite, synthetic mineral fibers and silicon carbide, with emphasis on potential carcinogenic effects.

Six years after the NRC review of EPA's Draft IRIS Toxicological Review of Formaldehyde: Regulatory implications of new science in evaluating formaldehyde leukemogenicity.

Shortly after the International Agency for Research on Cancer (IARC) determined that formaldehyde causes leukemia, the United States Environmental Protection Agency (EPA) released its Draft IRIS Toxicological Review of Formaldehyde ("Draft IRIS Assessment"), also concluding that formaldehyde causes leukemia. Peer review of the Draft IRIS Assessment by a National Academy of Science committee noted that "causal determinations are not supported by the narrative provided in the draft" (NRC 2011). They offered recommendations for improving the Draft IRIS assessment and identified several important research gaps.

Cancer Risk Associated With Exposure to Bitumen and Bitumen Fumes: An Updated Systematic Review and Meta-Analysis.

Objective: To evaluate whether cancer risks are increased among bitumen (asphalt) workers.

Methods: Systematic review and meta-analysis of cancer risks (lung, upper aerodigestive tract (UADT), esophagus, bladder, kidney, stomach, and skin) and bitumen exposure. Certainty in the epidemiological evidence that bitumen-exposed workers experience increased cancer risks was rated using Grading of Recommendations Assessment, Development and Evaluation criteria.

Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: mortality update through 2013.

Objective: To evaluate mortality risks of angiosarcoma of the liver (ASL), primary hepatocellular carcinoma (HCC) and other cancers among 9951 men employed between 1942 and 1972 at 35 US vinyl chloride (VC) or polyvinyl chloride plants followed for mortality through 31 December 2013.

Methods: SMR and time-dependent Cox proportional hazards analyses were used to evaluate mortality risks by cumulative VC exposure.

Results: Liver cancer mortality was elevated (SMR=2.

Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde-melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde.