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Results for “Biomarker variability”

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PubMed2006

Use of biomarkers in epidemiologic studies: minimizing the influence of measurement error in the study design and analysis.

The inclusion of biomarkers measured on the continuous scale, such as endogenous sex hormones or antioxidant levels, has become common in epidemiologic studies, and introduces additional sources of error that are specific to biomarkers. This includes error associated with specimen collection, processing, and storage; laboratory error (both within and between batch); and variability in the biomarker levels over time within an individual. In this review, we discuss and recommend study design and analytic strategies to deal with these sources of measurement error. In particular we describe methods to prevent or minimize some sources of error through appropriate sample collection and storage, communication with the laboratory, proper batching of samples, and participant matching. We also discuss how to quantify error related to biomarkers, focusing on issues of quality control, pilot studies, and how to measure within-person stability over time. Further, we discuss analytic issues for dealing with laboratory and within-person variability. Finally we recommend that journals standardize the reporting of biomarker assays in scientific manuscripts.

Biomarkers↗

PubMed2006

Measurements of biomarker levels in flounder (Platichthys flesus) and blue mussel (Mytilus trossulus) from the Gulf of Gdańsk (southern Baltic).

In the framework of the EU funded BEEP project a set of biomarkers, gross morphometric indices and tissue concentrations of selected organic pollutants were measured in flounder (Platichthys flesus) and mussels (Mytilus trossulus) collected twice a year (April and October) from three sites in the inner Gulf of Gdańsk between autumn 2001 and spring 2003. In flounder, seasonal differences in most biomarkers were observed, but no correlations with tissue pollutant levels could be found. In mussels, highly variable levels in biomarker responses were seen, but no clear seasonal or spatial trends, directly related to tissue concentrations, could be established. The observed biomarkers distribution the study sites are probably mostly caused by interannual, seasonal and individual variability and, in case of flounder, possibly by exchange of stocks between the sampling sites.

Acetylcholinesterase↗

PubMed2000

Biomarkers in zebra mussels (Dreissena polymorpha) for the assessment and monitoring of water quality of the St Lawrence River (Canada).

Five biomarkers (MT: metallothionein-like proteins, EROD: ethoxyresorufin ortho-dééthylase, DNA strand breaks, LPO: peroxidation of lipids, VG: vitellogenin-like protiens) were measured in the soft tissues of zebra mussels (Dreissena polymorpha) in order to assess the spatial variation of exposure to contaminants along the St Lawrence River (Canada). Fifteen mussels >25 mm shell length were analyzed from each of the 13 sampling sites. Significant differences between sites were noted for all biomarkers, but the general level of variability was low. Three biomarkers (DNA, LPO and VG) exhibited a similar pattern of spatial variation while MT and EROD had distinct and specific patterns. MT had the strongest discriminating power and EROD showed the largest range of variation among sites. Highest biomarker responses were measured in specimens from local contaminated sites such as harbors and industrial sectors. A positive relationship was found between MT and copper (Cu), but no significant correlation was observed between other biomarker responses and the levels of ten trace metals bioaccumulating in the zebra mussels tissues. Results indicate that the measurement of biomarker responses is technically feasible. The performance of each biomarker is assessed in the context of the role and advantages of selecting a battery of biomarkers for detecting contamination problems. The use of zebra mussels as a sentinel species for biomonitoring potential toxic effects in situ is discussed.

Journal Article↗

PubMed2002

Covariates and confounding in epidemiologic studies using metabolic gene polymorphisms.

The relationship between exposure and disease when biomarkers are introduced in an epidemiologic study is explored and summarized. In molecular epidemiologic studies, biologic measurements play a major role as markers of exposure, disease or susceptibility to disease and/or exposure. In this scenario, the definition and management of confounding factors may change. Sometimes the presence or activation of the biomarker is partially caused by the relevant environmental exposure, and therefore the 2 variables (exposure and biomarker) should not be always treated as confounders of each other. Models of exposure-disease association in the presence of biologic markers are presented. The concept of confounders is reviewed in light of the role of biomarkers in the pathway between exposure and disease.

Biomarkers↗

PubMed2000

Human variability in mercury toxicokinetics and steady state biomarker ratios.

Regulatory guidelines regarding methylmercury exposure depend on dose-response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose-response models. Most assessments have used point estimates for these ratios; however, significant interindividual and interstudy variability has been reported. For example, a maternal ratio of 250 ppm in hair per mg/L in blood is commonly used in models, but a 1990 WHO review reports mean ratios ranging from 140 to 370 ppm per mg/L. To account for interindividual and interstudy variation in applying these ratios to risk and safety assessment, some researchers have proposed representing the ratios with probability distributions and conducting probabilistic assessments. Such assessments would allow regulators to consider the range and like-lihood of mercury exposures in a population, rather than limiting the evaluation to an estimate of the average exposure or a single conservative exposure estimate. However, no consensus exists on the most appropriate distributions for representing these parameters. We discuss published reviews of blood-to-hair and blood-to-intake steady state ratios for mercury and suggest statistical approaches for combining existing datasets to form generalized probability distributions for mercury distribution ratios. Although generalized distributions may not be applicable to all populations, they allow a more informative assessment than point estimates where individual biokinetic information is unavailable. Whereas development and use of these distributions will improve existing exposure and risk models, additional efforts in data generation and model development are required.

Biomarkers↗

PubMed2005

Dietary intake assessments in epidemiology: can we know what we are measuring?

PURPOSE: We discuss fundamental assumptions required for the validation of dietary questionnaire assessments, using latent variable models. METHODS: We discuss some methodological aspects of latent variable modelling in terms of the triad method, for comparisons between questionnaire assessments, food consumption records and/or biomarkers. In particular, we address the recent proposal (Frazer et al) that biases due to correlated random errors between different measurement types could be overcome by using two biomarkers as instrumental variables, as recently proposed by. RESULTS: The instrumental variable approach proposed by Frazer et al, but also other validation models proposed so far, require the assumption that questionnaire measurements are specific for a defined type of food or nutrient intake (latent variable of interest) - that is, conditionally on the true intake levels of this food or nutrient the questionnaire measurements should have no association with intakes of any other dietary component. CONCLUSION: More methodological research is needed on the design of multivariate validation studies that might allow the examination of measurement specificity in practice.

Data Collection↗

PubMed2001

Developing sustainable studies on environmental health.

Toxicogenetics, toxicogenomics and proteomics are providing new biomarkers for use in human studies. These, coupled with the more traditional biological responses currently in use, provide a vast armamentarium for assessing exposures, effects and susceptibility factors relating to environmental pollutants. Biomarker availability, however, does not automatically translate to usefulness for studies directed at human health improvement. Transitional studies bridging the gap between laboratory and field, with the biomarker as dependent variable, are required for validation for intended applications. Prospective or cross-sectional studies are usually optimal for validating biomarkers of exposure, where the biomarker response follows the event (exposure) and the entire study population is affected. Biomarkers of effect, where the event (outcome) follows the biomarker response and may be infrequent in the study population, present more complex problems. Identification of genotypes as susceptibility factors requires that additional issues be addressed. Despite these difficulties, new data are emerging from transitional investigations that are providing validated biomarkers for sustainable human studies. It is now possible to envision schemes for integrating the results of molecular epidemiological investigations into the general toxicological evaluations of environmental agents. These will allow intermediate endpoints to be used for making realistic human health assessments and for elucidating pathogenic mechanisms that identify targets for intervention, all with the goal of preventing environmentally mediated human disease. Finally, select biomarker responses that predict the likelihood of disease occurrence will find application in the interpretation of individual medical diagnostic tests, with the goal of improving cancer detection and management.

Animals↗

PubMed2002

Cartilage-derived biomarkers of osteoarthritis in synovial fluid of dogs with naturally acquired rupture of the cranial cruciate ligament.

OBJECTIVE: To compare synovial fluid biomarkers of cartilage metabolism in joints with naturally acquired or experimentally induced cranial cruciate ligament (CCL) rupture and determine correlations with stage and severity of disease in dogs. ANIMALS: 95 dogs with ruptured CCL, 8 dogs with experimentally ruptured CCL, and 24 healthy dogs. PROCEDURES: Synovial fluid was assayed for chondroitin sulfate neo-epitopes 3B3(-) and 7D4 and glycosaminoglycan (GAG) concentration. Results were correlated with demographic data, duration of lameness, radiographic osteoarthritis score, and intra-articular lesions. RESULTS: The 7D4 concentrations and 7D4:GAG in synovial fluid from joints with naturally acquired CCL rupture and experimental CCL transection were similar and significantly greater than values for healthy control joints. The 3B3(-) concentrations in the CCL-deficient groups were not significantly different, although only values in the naturally acquired CCL rupture group were significantly greater than those in the healthy control group. Within the naturally acquired CCL rupture group there was a significant correlation between 3B3(-) and 7D4 concentrations. However, there were no significant correlations between biomarker concentrations and continuous demographic or disease-related variables or differences in biomarker concentrations with different categories of disease. CONCLUSIONS AND CLINICAL RELEVANCE: Synovial fluid biomarker concentrations were significantly increased in joints with secondary osteoarthritis associated with naturally acquired or experimental CCL rupture; however, lack of apparently simple relationships with demographic variables or stage or severity of disease limits their clinical usefulness.

Animals↗

PubMed2005

A dietary pattern protective against type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)--Potsdam Study cohort.

AIMS/HYPOTHESIS: The aim of this study was to identify a dietary pattern associated with diabetes-related biomarkers and to investigate whether this pattern is associated with the incidence of type 2 diabetes. METHODS: A nested case-control study of 192 cases of incident type 2 diabetes and 382 control subjects matched for sex and age was conducted. All subjects were participants in the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Dietary pattern score was derived using intake data on 48 food groups as exposure variables and the biomarkers HbA1c, HDL cholesterol, C-reactive protein and adiponectin as response variables in reduced rank regression. The association of the score with diabetes risk was estimated by conditional logistic regression analysis. RESULTS: A high score for the identified dietary pattern was characterised by a high intake of fresh fruit and a low intake of high-caloric soft drinks, beer, red meat, poultry, processed meat, legumes and bread (excluding wholegrain bread). Subjects with high scores had high plasma concentrations of HDL cholesterol and adiponectin and low plasma concentrations of HbA1c and C-reactive protein. After multivariate adjustment, the odds ratios for type 2 diabetes across increasing quintiles of the dietary pattern score were 1.0, 0.59, 0.51, 0.26 and 0.27, respectively (p = 0.0006 for trend). CONCLUSIONS/INTERPRETATION: A high score for the identified dietary pattern is associated with a more favourable biomarker profile and a substantially reduced incidence of type 2 diabetes.

Adiponectin↗

PubMed2005

Cartilage biomarkers in ankylosing spondylitis: relationship to clinical variables and treatment response.

OBJECTIVE: Ankylosing spondylitis (AS) is a progressive disease in which chronic inflammation can lead to extensive new bone formation throughout the spine. At present, few measures of the activity or extent of the disease are available. In this study, we sought to determine whether markers of cartilage synthesis and degradation could provide such quantitative measures. METHODS: Serum samples from 23 patients receiving infliximab treatment for AS were obtained at baseline and at weeks 2, 6, 14, and 22. Patients were stratified with respect to joint involvement and baseline levels of inflammatory markers, and responders were defined according to the Assessments in Ankylosing Spondylitis 20% criteria. Serial measurements of interferon-gamma, tumor necrosis factor alpha, transforming growth factor beta (TGFbeta), interleukin-10 (IL-10), and IL-1 were done at each time point. The following biomarkers were measured by enzyme-linked immunosorbent assay: the proteoglycan aggrecan 846 epitope, a marker of cartilage turnover; C-propeptide of type II collagen (CPII), a biosynthesis marker; and the Col2-3/4(long mono) (C2C) and Col2-3/4(short) (C1-2C) neoepitopes, reflecting collagen cleavage of type II collagen and type I/type II collagen, respectively. RESULTS: At baseline, patients with AS demonstrated significant elevations in serum levels of CPII, the 846 epitope, and the CPII-to-C2C (CPII:C2C) ratio (but not C2C or C1-2C) compared with normal controls. Of the biomarkers examined, only CPII:C2C showed a correlation with the C-reactive protein (CRP) level. Among the biomarker-cytokine relationships, TGFbeta demonstrated a trend toward a positive correlation with the 846 epitope. CONCLUSION: In AS, elevated serum levels of CPII and the 846 epitope may be related to biosynthetic turnover of hyaline cartilage and the intervertebral discs but may also reflect progressive bone formation as a result of endochondral ossification. The correlation of the CPII:C2C ratio with CRP suggests that the CPII:C2C ratio might prove to be a useful marker of disease activity in AS.

Adult↗

PubMed2005

Determinants of temporal variability in NHEXAS-Maryland environmental concentrations, exposures, and biomarkers.

The longitudinal NHEXAS-Maryland study measured metals, PAHs, and pesticides in several media to capture temporal variability. Questionnaires were concurrently administered to identify factors that influenced changes in contaminant levels over time. We constructed mixed-effects regression models for lead, phenanthrene, and chlorpyrifos (including metabolites) in indoor air, dust, dermal wipes, and biological fluids. Significant predictors represented time-varying activities as well as unchanging housing and demographic factors. There was little overlap among the models, with predictors generally reflecting the diverse characteristics of the target compounds. We estimated between- and within-person variance components to evaluate the reliability of the measurements. While only one measurement of lead in blood or chlopyrifos in dust was needed for a dependable estimate of an individual's average level, three to eight measurements were needed for most other compound/exposure medium combinations because of considerable temporal variability. Measurements in biological fluids and dust were generally more consistent than those in indoor air. The significant covariates in the full models preferentially reduced the between-person variance component. Since the regression models explained only 1-37% of the within-person variance, the questionnaires in this study provided only modest insight into the factors responsible for the temporal variability in the contaminant levels.

Air Pollution, Indoor↗

PubMed1994

Standardization of immunobioassays as surrogate endpoints.

Despite centuries of scientific inquiry and medical effort, breast cancer remains one of the most dreaded human illnesses, emphasizing the need for prevention, early detection, and better management of these patients. Currently, newly recognized biomarkers are being examined as prognostic indicators to identify potentially aggressive cancers and to aid in planning treatment. Although the new prognostic factors are not yet firmly established, recent insights coupled with the availability of new biological markers have provided an opportunity to understand the initial genetic events leading to the development of breast cancer. Knowledge about those genetic events may provide opportunities for prophylactic intervention, improve our ability to predict breast cancer risk, and lead to strategies for early detection. Attention has focused on histomorphological changes and, to a lesser extent, cytomorphological changes in breast lesions associated with increased risk for subsequent breast cancer. However, the goal underlying the detection of early breast cancer is to distinguish patients who will develop breast cancer from those who will not. This task involves complex issues surrounding the selection, validation, quantitation, standardization, and population application of breast cancer biomarkers, and perhaps designing a protocol to control four major sources of cancer marker variability which may confound biomarker clinical application. These include biological and sampling diversity, variability of detection procedures, and validation against acknowledged disease endpoints. Immunocytochemistry has been applied extensively to assess the pattern of expression of different biomarkers in breast cancer. Immunocytochemical assays have permitted the localization of estrogen and progesterone receptors, oncogenes and tumor suppressor genes, growth factors, and other constituents at the cellular level, and also facilitated correlative analysis of morphology with specific expression of gene products.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗

PubMed1998

Seasonal variation of biochemical indexes of bone turnover: results of a population-based study.

Biochemical markers of bone turnover have been shown to provide valuable information for the diagnosis and monitoring of metabolic bone disease. However, these dynamic indexes are influenced by a number of factors that need to be clearly identified to improve their clinical usefulness. To evaluate the contributions of anthropometric, life style, and environmental variables on bone turnover, biochemical markers of bone metabolism were determined in a population-based sample of 580 adults, aged 50-81 yr (297 men and 283 women). Subjects were recruited during 14 consecutive months within the framework of the European Vertebral Osteoporosis Study. Serum total and bone-specific alkaline phosphatase (S-BAP), serum C-terminal propeptide of type I collagen, and serum osteocalcin (S-OC) were measured as bone formation markers. Urinary total pyridinoline and deoxypyridinoline were included as bone resorption indexes. In females, serum levels of 25-hydroxyvitamin D3 were significantly higher (P < 0.01) in summer (May-September) than in winter (October-April), whereas no significant differences were found in males. In both sexes, no seasonal changes were seen in serum PTH. In males, serum total alkaline phosphatase (P < 0.01), S-BAP (P < 0.001), and S-OC (P < 0.05) were significantly higher in winter than in summer. During the same period, females had higher values of S-BAP (P < 0.05), S-OC (P < 0.01), and urinary pyridinoline and deoxypyridinoline (P < 0.001, respectively). Univariate analyses of the effects of life style habits on markers of bone metabolism revealed that in females, regular alcohol consumption and current smoking led to a suppression of markers of bone turnover, whereas in males, only alcohol intake was associated with such changes. In contrast, physical activity was associated with higher levels of bone formation markers and reduced levels of bone resorption indexes in both sexes. As shown by multivariate regression analyses, seasonal variations accounted for more of the variability in most biomarkers (up to 12%) than any of the other anthropometric or life style factors except age. This effect may be attributed to subclinical vitamin D deficiency during the winter period, which is common in countries of the northern hemisphere. We conclude that seasonal variation contributes significantly to the biological variability of bone turnover and needs consideration when interpreting the results of bone marker measurements.

Aged↗

PubMed2004

Smoking status and occupational exposure affects oxidative DNA injury in boilermakers exposed to metal fume and residual oil fly ash.

Epidemiologic studies demonstrate increased cancer incidence among workers exposed to polycyclic aromatic hydrocarbons (PAH) and metals, probably through cumulative oxidative DNA damage in response to carcinogens. Boilermakers are exposed to particulates of residual oil fly ash (ROFA) and metal fume that contain carcinogenic PAH and metals. We conducted a repeated-measures cohort study in boilermakers during the overhaul of an oil-fired boiler to determine a possible association between the level of 8-hydroxy-2'-deoxyguanosine (8-OH-dG; an oxidative injury biomarker) and biomarkers of PAH (1-hydroxypyrene; 1-OHP) and metal exposure. Preshift and postshift urine samples were analyzed for 8-OH-dG, cotinine, 1-OHP, and metals. Generalized estimating equations were used to model the multivariate relationship of 8-OH-dG to the explanatory variables of interest. Biomarker levels were determined for 181 urine samples from 20 male subjects (mean age 45 years, 50% smokers). Metal and 1-OHP levels increased cross-week and were affected by smoking status. Levels of 8-OH-dG were higher in nonsmokers at the start of the workweek yet declined after occupational exposure to similar levels as in smokers. Multivariate analysis indicated that metal x cotinine interaction terms for nickel, vanadium, chromium, and copper were significantly associated with the 8-OH-dG level, but there were differential effects depending on the metal. This study suggests that oxidative DNA damage in boilermakers is influenced by the interaction between occupational exposures and smoking status. In addition, boilermakers may have reduced ability to repair damaged DNA after ROFA and metal fume exposure. This finding has clinical relevance because these exposures may increase the cancer susceptibility of boilermakers.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

High-throughput optimization by statistical designs: example with rat liver slices cryopreservation.

The purpose of this study was to optimize cryopreservation conditions of rat liver slices in a high-throughput format, with focus on reproducibility. A statistical design of 32 experiments was performed and intracellular lactate dehydrogenase (LDHi) activity and antipyrine (AP) metabolism were evaluated as biomarkers. At freezing, modified University of Wisconsin solution was better than Williams'E medium, and pure dimethyl sulfoxide was better than a cryoprotectant mixture. The best cryoprotectant concentrations were 10% for LDHi and 20% for AP metabolism. Fetal calf serum could be used at 50 or 80%, and incubation of slices with the cryoprotectant could last 10 or 20 min. At thawing, 42 degrees C was better than 22 degrees C. After thawing, 1h was better than 3h of preculture. Cryopreservation increased the interslice variability of the biomarkers. After cryopreservation, LDHi and AP metabolism levels were up to 84 and 80% of fresh values. However, these high levels were not reproducibly achieved. Two factors involved in the day-to-day variability of LDHi were identified: the incubation time with the cryoprotectant and the preculture time. In conclusion, the statistical design was very efficient to quickly determine optimized conditions by simultaneously measuring the role of numerous factors. The cryopreservation procedure developed appears suitable for qualitative metabolic profiling studies.

Animals↗

PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗

PubMed1985

A study of multiple biological markers in twins.

Genetic and environmental influences on the phenotypic expressions of several biological markers were studied in 18 monozygous (MZ) and 8 dizygous (DZ) twin pairs. Zygosity was determined using ABO, Rh, and HLA. The biomarkers studied included: T & B lymphocytes, suppressor and helper T lymphocytes (T gamma, T mu), T cell (PHA) mitogen activation (MA), serum immunoglobulins (IgA, IgM, and IgG), plasma carcinoembryonic antigen (CEA), aryl-hydrocarbon hydroxylase (AHH) and sister chromatid exchange (SCE) in lymphocytes. Temporal variation of markers over a 6-month period was not significant. The mean absolute differences between levels from first and second blood draws were less than one standard deviation. Variability associated with age was not significant. Females had higher levels of T lymphocytes than males. A gender related association was observed for the IgM immunoglobulin test: females had a higher mean level of IgM. Smoking was found to influence the levels of SCE, T helper lymphocytes and mitogen activation. The variability of these biomarkers within and between twin pairs was quantified. Immunoglobulin levels, particularly that of IgM, showed statistically greater similarity within MZ twins than within DZ twins. Several other markers suggested heritability.

Adult↗

PubMed2001

Metabolic polymorphisms and urinary biomarkers in subjects with low benzene exposure.

The effect of some common metabolic polymorphisms on the rate of trans,trans-muconic acid (TMA) and S-phenylmercapturic acid (SPMA) excretion was investigated in 169 policemen exposed to low benzene levels (<10 microg/m3) during the work shift. End-shift urinary concentrations of TMA and SPMA, normalized to unmetabolized blood benzene concentration, were used as indicators of individual metabolic capacity. CYP2E1, NQO1, GSTM1, and CSTT1 polymorphisms were analyzed in all subjects by polymerase chain reaction (PCR) restriction fragment length (RFL). The results obtained show significantly elevated levels of TMA and SPMA in urine of smokers compared to nonsmokers, whereas no correlation with environmental benzene was observed. TMA/blood benzene ratio was partially modulated by glutathione S-transferase (GST) genotypes, with significantly higher values in null individuals (GSTM1 and GSTT1 combined). However, a greater fraction of total variance of TMA/blood benzene in the study population was explained by other independent variables, that is, season of sampling, smoking habits, and gender. Variance in SPMA/blood benzene ratio was only associated with smoking and occupation, whereas no significant role was observed for the metabolic polymorphisms considered. These results suggest that in a population exposed to very low benzene concentrations, urinary TMA and SPMA levels are affected to a limited extent by metabolic polymorphisms, whereas other factors, such as gender, lifestyle, or other confounders, may account for a larger fraction of the interindividual variability of these biomarkers.

Acetylcysteine↗