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PubMed1995

Overview of preventable industrial causes of occupational cancer.

This paper summarizes what is known about preventable causes of occupational cancer, including single agents, complex mixtures, and broad occupational associations. Epidemiologic methods have been very successful in documenting cancer risks associated with single agents. Epidemiologic data are most conclusive when an exposure-response relationship can be demonstrated. Examples of agents for which epidemiologic studies provide evidence of an exposure-response relationship include benzene and (concurrent exposure to) ortho-toluidine and aniline. Vinyl chloride and bischloromethyl ether are examples of associations between single agents and rare histologic types of cancer. It is more difficult to conduct epidemiologic studies to identify cancer risks associated with complex mixtures. Studies of diesel exhaust and lung cancer and metal machining oils are cited as having employed advanced industrial hygiene and epidemiologic methods for studies of complex mixtures. Elevated cancer risks have also been identified in broad occupational groups, including painters and dry cleaners. Epidemiologic case-control studies are often used to detect such associations but are limited in their abilities to detect the causal agents. Major gaps exist in knowledge of occupational cancer risks among women workers and workers of color. Because epidemiologic research measures illness and mortality that have already occurred, a positive study can be interpreted to represent a failure in prevention. The challenge we face in the next decade is to identify interventions earlier in the causal pathway (toxicologic testing, biomarkers of exposure or precancerous changes, institution of engineering and good industrial hygiene practices to reduce occupational exposure levels) so that occupational cancer can be prevented.

Carcinogens↗
PubMedDate not supplied

Methodologies for measuring carcinogen adducts in humans.

In summary, although some of the more optimistic aspirations for human biomonitoring studies envisaged a decade ago have not been realized thus far, some considerable advances have been made. The examples cited above indicate that the feasibility of biomonitoring has been clearly established. In addition, they demonstrate the need for preliminary biomarker testing and validation through transitional studies prior to their field application. In the next decade of research into carcinogen adducts in humans, continued improvements in the reproducibility and specificity of assays for DNA adducts will be needed. Perhaps the increasing use of hybrid methodologies to concentrate adducts followed by specific chemical analyses will allow such adducts to be monitored more precisely. Of course, further basic research into the mechanisms of carcinogenesis will allow the measurement of specific novel markers which are more closely tied to the disease endpoint than adducts. The development of new assays for determining metabolic phenotypes and genotypes relevant to carcinogenesis should improve our estimates of susceptibility (46-48). Such new approaches along with the sustained improvement of current assays will allow molecular approaches to continue to enrich cancer epidemiology in the future.

Carcinogens↗
PubMed2005

Point-of-Care Testing and Cardiac Biomarkers: The Standard of Care and Vision for Chest Pain Centers.

Point-of-care testing (POCT) is defined as testing at or near the site of patient care. POCTdecreases therapeutic turnaround time (TTAT), increases clinical efficiency, and improves medical and economic outcomes. TTAT represents the time from test ordering to patient treatment. POC technologies have become ubiquitous in the United States, and, therefore,so has the potential for speed, convenience, and satisfaction, strong advantages for physicians, nurses, and patients in chest pain centers. POCT is applied most beneficially through the collaborative teamwork of clinicians and laboratorians who use integrative strategies, performance maps, clinical algorithms, and care paths (critical pathways). For example, clinical investigators have shown that on-site integration of testing for cardiac injury markers (myoglobin, creatinine kinase myocardial band [CKMB],and cardiac troponin I [cTnI]) in accelerated diagnostic algorithms produces effective screening, less hospitalization, and substantial savings. Chest pain centers, which now total over 150 accredited in the United States, incorporate similar types of protocol-driven performance enhancements. This optimization allows chest pain centers to improve patient evaluation, treatment, survival, and discharge. This article focuses on cardiac biomarker POCT for chest pain centers and emergency medicine.

Acute Disease↗
PubMed1998

Biochemical and molecular neurotoxicology: relevance to biomarker development, neurotoxicity testing and risk assessment.

Biochemical and molecular approaches are most useful to define potential mechanisms of neurotoxicity. Information on the mechanisms of action of neurotoxicants can play a key role in neurotoxicology by allowing, among others, the development of potential biomarkers of effect, the refinement of in vitro testing procedures, and the improvement of the risk assessment process. An important class of insecticides, the organophosphates, are discussed as an example of how knowledge of molecular mechanisms is useful in various aspects of neurotoxicology. The utilization of such information in the area of biomarkers of exposure and effects, and of in vitro testing is presented. Additionally, mechanistic issues related to genetic polymorphisms and risk assessment are discussed.

Animals↗
PubMed2002

Cardiac markers for myocardial infarction. A brief review.

Blood testing for biomarkers of myocardial injury plays an increasingly important role for the evaluation, diagnosis, and triage of patients with chest pain. The guidelines for the diagnosis of myocardial infarction (MI) have recently changed and prominently incorporate the results of cardiac marker testing in the clinical definition of MI. We review these updated guidelines for MI definition as it pertains to cardiac biomarker testing and further compare the differing biology and release kinetics of clinically relevant biomarkers. Finally, we define the contemporary use of cardiac biomarker testing for patients with chest pain, including appropriate integration of point-of-care testing into day-to-day clinical use.

Biomarkers↗
PubMed1993

Application of the urinary S-phenylmercapturic acid test as a biomarker for low levels of exposure to benzene in industry.

Recently, the determination of S-phenylmercapturic acid (S-PMA) in urine has been proposed as a suitable biomarker for the monitoring of low level exposures to benzene. In the study reported here, the test has been validated in 12 separate studies in chemical manufacturing plants, oil refineries, and natural gas production plants. Parameters studied were the urinary excretion characteristics of S-PMA, the specificity and the sensitivity of the assay, and the relations between exposures to airborne benzene and urinary S-PMA concentrations and between urinary phenol and S-PMA concentrations. The range of exposures to benzene was highest in workers in chemical manufacturing plants and in workers cleaning tanks or installations containing benzene as a component of natural gas condensate. Urinary S-PMA concentrations were measured up to 543 micrograms/g creatinine. Workers' exposures to benzene were lowest in oil refineries and S-PMA concentrations were comparable with those in smoking or nonsmoking control persons (most below the detection limit of 1 to 5 micrograms/g creatinine). In most workers S-PMA was excreted in a single phase and the highest S-PMA concentrations were at the end of an eight hour shift. The average half life of elimination was 9.0 (SD 4.5) hours (31 workers). Tentatively, in five workers a second phase of elimination was found with an average half life of 45 (SD 4) hours. A strong correlation was found between eight hour exposure to airborne benzene of 1 mg/m3 (0.3 ppm) and higher and urinary S-PMA concentrations in end of shift samples. It was calculated that an eight hour benzene exposure of 3.25 mg/m3 (1 ppm) corresponds to an average S-PMA concentration of 46 micrograms/g creatinine (95% confidence interval 41-50 micrograms/g creatinine). A strong correlation was also found between urinary phenol and S-PMA concentrations. At a urinary phenol concentration of 50 mg/g creatinine, corresponding to an eight hour benzene exposure of 32.5 mg/m3 (10 ppm), the average urinary S-PMA concentration was 383 micrograms/g creatinine. In conclusion, with the current sensitivity of the test, eight hour time weighted average benzene exposures of 1 mg/m3 (0.3 ppm) and higher can be measured.

Acetylcysteine↗
PubMed1991

Use of laboratory tests for immune biomarkers in environmental health studies concerned with exposure to indoor air pollutants.

The immune system is likely to be involved in some of the health effects caused by certain indoor air exposures, and immune biomarkers can help determine which exposures and health effects have important immune components. However, the lack of standardized laboratory tests for most human immune markers and the many confounding variables that can influence them makes interpretation of results for exposure and disease end points uncertain. This paper presents an overview of the immune system and the considerations involved in using tests for immune markers in clinical epidemiology studies, particularly those concerned with indoor air exposures. Careful study design, well-characterized laboratory methods, and rigorous documentation of exposure status are required to determine the predictive value of such tests. Clinical tests currently available for some immune markers could help identify and characterize both irritative and hypersensitivity reactions to indoor air pollutants. Newer tests developed in research settings might provide more incisive indicators of immune status that could help identify exposure, susceptibility, or preclinical disease states, but their methodologies must be refined and tested in multicenter studies before they can be used reliably in public health applications.

Air Pollutants↗
PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗
PubMed2002

Evaluation of quantitative cardiac biomarker point-of-care testing in the emergency department.

This study was undertaken to evaluate the diagnostic accuracy and practicality of Emergency Department (ED) testing for cardiac biomarkers in the diagnosis of acute coronary syndromes. All patients presenting with chest pain to the ED of a community-based tertiary care facility over a 16-day period (N = 205) had blood drawn and tested for cardiac troponin I, myoglobin, and CK-MB by a quantitative, point-of-care instrument system (Stratus CS). Point-of-care cardiac testing expedited diagnosis by decreasing the turn-around time by 55% compared to the central laboratory. The extreme sensitivity of the cardiac troponin I assay integral to this system was responsible for the high diagnostic accuracy (100% sensitivity; virtually 100% specificity, compared with the final assigned diagnosis). The assay also identified a clinically significant "high-risk" zone for near-future cardiac events: 17 patients were identified and four of these progressed to further cardiac events in the next 9 months. Further studies to explore the clinical implications of this high-risk zone are warranted.

Angina, Unstable↗
PubMed2003

Correlations of breast carcinoma biomarkers and p53 tested by FASAY and immunohistochemistry.

p53 status is an important predictive factor in breast cancer, but the results of many studies are ambiguous. We tested p53 by functional analysis of separated alleles in yeast (FASAY) as well as by immunohistochemistry (IHC) and evaluated correlations with main prognostic factors, proliferation, and Bcl-2. Thirty-two tumors were tested with antibodies BP53-12, DO1, DO11, DO12, and by FASAY. Spearman rank correlations were tested separately with age, tumor type, pT, grade, pN, NPI, Ki-67, S-phase, proliferation index, Bcl-2, and steroid receptor status determined by ER, PR, and pS2. FASAY showed significant correlations with ductal type, grade and proliferation, and an inverse correlation with functional estrogen receptor and Bcl-2. FASAY provided better correlations compared to p53 IHC. We conclude that FASAY shows significant correlations with main prognostic/predictive factors and provides more reliable biological information compared to p53 IHC. Apoptosis is positively linked to proliferation and is not under the control of p53, which is frequently mutated in highly proliferating carcinomas. FASAY seems to be very important in assessing the predictive significance of p53 for a specific therapy of breast cancer.

Adult↗
PubMed2002

The cytotoxic and genotoxic potential of surface water and wastewater effluents as determined by bioluminescence, umu-assays and selected biomarkers.

Two bacterial tests employing Photobacterieum phosphoreum (Microtox bioluminescence test) and Salmonella typhimurium TA 1535 pSK1002 (umu-assay) were evaluated to estimate the cytotoxic and genotoxic potential of water samples from the selected rivers in Germany as well as the primary and secondary effluents of some sewage treatment plants. Rainbow trout (Onchorynchus mykiss) were exposed to different concentrations (20-40%) of secondary effluent in the model online aquatic monitoring plant WaBoLu-Aquatox. The toxic potential of water samples from the exposure tanks was determined in two prokaryotic test systems and the biomarkers acethylcholinesterase (AChE) activity in muscle tissue and DNA unwinding assay in liver tissue of fish. Samples from the tested rivers showed no inhibition of the bioluminescence of P. phosphoreum or growth of umu-bacteria. Only primary effluent samples from the treatment plants at the Saale River inhibited the light emission or the growth of test bacteria by more than 20%. The induction ratio of umu-bacteria was in most of the river samples less than the threshold for genotoxicity (IR < 1.5). Only some samples from the Saale River, especially at sites downstream of secondary effluents caused genotoxic responses in the umu-assay. Samples of primary effluents contained the greatest genotoxic potential up to GEUI = 6 which was not detectable in samples of secondary effluents. A concentration range 20-40% secondary effluent inhibited AChE activity in muscle tissue and significantly increased DNA fragmentation in liver tissue of rainbow trout. In contrast, no cytotoxic or genotoxic responses in the umu-assay were caused by water samples. Both bacterial methods can be successfully used to analyse the cytotoxic and genotoxic response of industrial and domestic wastewater and to estimate the effectiveness of sewage treatment units. However, because of their low sensitivity and high susceptibility, they are not reliable as a single test for the detection of cytotoxicity and genotoxicity in surface water. The application of prokaryotic tests systems with biomarkers such as AChE activity and DNA fragmentation in different tissues of test organisms seems to be a useful combination for the assessment of cytotoxic and genotoxic potential in surface water and secondary effluent.

Acetylcholinesterase↗
PubMed2005

Using the nucleolar biomarker and the micronucleus test on in vivo fish fin cells.

This study was aimed at developing the nucleolar biomarker and the micronucleus test on in vivo fish fin cells for assessing water cytotoxicity and genotoxicity. Both biomarkers can be used either jointly or separately on fins of the same fish during the experiment. For studying the nucleolar characteristics, small pieces of the fin edge were cut several times during 30-180 min of fish exposure. For micronucleus testing, the fin tissue regenerating after its cutting was investigated after 2-5 days of fish incubation. Effects of copper (0.1 and 2.5 mg/L), cadmium (0.005 and 1.0 mg/L) ions and chloral hydrate (400 and 800 mg/L) solutions were studied on cells of common carp (Cyprinus carpio L.), crucian carp (Carassius auratus gibelio Bloch.), and Mozambique tilapia (Tilapia (Sautherodon) mossambica) using a set of nucleolar characteristics (the number of nucleoli per cell, the size of a single nucleolus, and the percentage of cells with heteromorphic paired nucleoli) and the frequencies of cells with micronuclei and double nuclei. Substantial changes in parameters of nucleolar activity of fin cells were found to be caused by cadmium and copper impact. In comparison to blood cells, gill and fin cells were more sensitive as demonstrated by their nuclear damages after the chloral hydrate influence. Fin cells were useful to determine periodically cytotoxic and genotoxic effects of organic and inorganic substances in the same individual fish without any disruption of its physiological functions.

Animals↗
PubMed2004

Potential drug interactions with the percent carbohydrate-deficient transferrin (%CDT) test, a new alcohol biomarker.

STUDY OBJECTIVE: To determine the effects of drugs on levels of carbohydrate-deficient transferrin (CDT), using the %CDT test, a new alcohol biomarker, in patients receiving drug therapy for chronic medical conditions such as diabetes mellitus, hypertension, and lipid disorders. DESIGN: Regression analysis of transformed data. SETTING: Eight primary care clinics in central Wisconsin. PATIENTS: Seven hundred ninety-nine primary care patients who were prescribed drug therapy for a variety of chronic illnesses such as diabetes, hypertension, and lipid disorders. MEASUREMENTS AND MAIN RESULTS: The %CDT level, 30-day history of alcohol consumption, symptoms of alcohol abuse or dependence, health status, and prescribed drugs were determined for each patient. All prescribed drugs that were taken by the patients in the last month were determined by self-report, medical records, or pharmacy records. Of the 799 patients, 89 were receiving drug therapy for diabetes, 299 for hypertension, 209 for both diabetes and hypertension, and 202 for medical conditions other than diabetes or hypertension. A regression analysis was performed after the data were transformed. Alcohol consumption, sex, age, tobacco use, and 20 drug classes were entered into the model. Factors associated with increased %CDT levels were alcohol consumption, female sex, and bupropion use. Two additional drug classes, the angiotensin II receptor blockers and the tricyclic antidepressants, were associated with lower %CDT levels. The effects of bupropion and tricyclic antidepressants on %CDT levels, however, appear to be confounded by alcohol intake. CONCLUSION: This study suggests that only one of 20 drug classes-the angiotensin II receptor blockers-affected %CDT levels in our primary care sample. Additional research with larger samples is needed to focus on the effects of individual drugs used in general clinical settings on %CDT levels.

Adult↗
PubMed2005

Effects of male reproductive toxicants on gene expression in rat testes.

Predictive biomarkers of testicular toxicity are needed for an efficient development of drugs. The purpose of the present study was to obtain further insight into the toxicity mechanisms of various male reproductive toxicants and to detect genomic biomarkers for rapid screening of testicular toxicity. Four reproductive toxicants, 2,5-hexanedione (Sertoli cells toxicant), ethylene glycol monomethyl ether (EGME; spermatocytes toxicant), cyclophosphamide (spermatogonia toxicant) and sulfasalazine, were orally administered to male rats once. Six hours after the single dosing, gene expression in the testes was monitored by cDNA microarray and real-time RT-PCR and the testes were histopathologically examined. No histopathological abnormality was detected except for slight degeneration of spermatocytes in the EGME-treated testes. cDNA microarray analysis revealed differential gene expression profiles, and it was possible based on the profiles to characterize the action of the compounds in the testes. Interestingly, 3 spermatogenesis-related genes -- heat shock protein 70-2, insulin growth factor binding protein 3 and glutathione S transferase pi -- were affected by all the compounds. The above changes of gene expression were detectable within a short period after the dosing prior to the appearance of obvious pathological changes. These data suggest that cDNA microarray is a useful technique for evaluation of primary testicular toxicity. Furthermore, we propose the above 3 spermatogenesis-related genes as potential biomarkers of testicular toxicity.

Administration, Oral↗