Biomarkers of occupational exposure do anticancer agents: a minireview

The majority of anticancer agents has in common DNA-damaging properties and affects not only target-cells but also non-tumour cells. Its genotoxicity has been demonstrated in experimental models and in cancer patients treated with chemotherapy. Health care personnel involved in the preparation and administration of chemotherapy is therefore at risk for adverse health effects, since most environmental sampling studies demonstrated that there is widespread contamination of work surfaces and equipments with anticancer drugs. Adherence to safety guidelines and proper use of personal protective equipment are insufficient to prevent significant absorption, as evidenced by the presence of detectable amounts of drugs in urine samples and increased frequency of genotoxicity biomarkers. In this minireview, a critical appraisal of the most important biomarkers used for the evaluation of occupational exposure to anticancer agents as well as a summary of the key findings from several studies published in this field is performed.     

Evaluation of concentration–response options for diacetyl in support of occupational risk assessment

The current emphasis on occupational exposures to diacetyl has led to new research on its effects. We evaluated whether the data are sufficient to support a transition from a hazard-based risk management approach to a quantitative occupational risk assessment approach, characterized by developing a health-based occupational exposure limit (OEL). Inhalation health effects data were evaluated and issues and uncertainties related to occupational risk assessment needs were identified. A systematic hazard characterization, supported by both the toxicology and epidemiology literature, showed that the respiratory tract effects of diacetyl are the primary end points of relevance for developing an OEL. In an effort to provide a systematic approach for the analysis of the issues that need to be considered in developing an occupational risk assessment for diacetyl, a potential OEL was derived. A concentration–response assessment was completed using tracheobronchial effects in mice as the critical effect. The resulting benchmark concentration (lower bound estimate or BMCL) was adjusted to a human equivalent concentration of 1.8 ppm. A composite uncertainty factor of 10 was recommended to account for extrapolation from an adjusted BMCL from an animal study and for human variability in sensitivity and taking into account other uncertainties in the overall database. The resulting OEL recommendation of 0.2 ppm as a time-weighted average (TWA) was supported by the current occupational epidemiology literature. This evaluation showed that a health-based OEL value can be derived for diacetyl with moderate to high confidence.     

Occupational exposure limits: a comparative study

Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.     

Derivation of an occupational exposure limit for inorganic borates using a weight of evidence approach

Inorganic borates are encountered in many settings worldwide, spurring international efforts to develop exposure guidance (US EPA, 2004; WHO, 2009; ATSDR, 2010) and occupational exposure limits (OEL) (ACGIH, 2005; MAK, 2011). We derived an updated OEL to reflect new data and current international risk assessment frameworks. We assessed toxicity and epidemiology data on inorganic borates to identify relevant adverse effects. International risk assessment frameworks (IPCS, 2005, 2007) were used to evaluate endpoint candidates: reproductive toxicity, developmental toxicity, and sensory irritation. For each endpoint, a preliminary OEL was derived and adjusted based on consideration of toxicokinetics, toxicodynamics, and other uncertainties. Selection of the endpoint point of departures (PODs) is supported by dose–response modeling. Developmental toxicity was the most sensitive systemic effect. An OEL of 1.6 mg B/m³ was estimated for this effect based on a POD of 63 mg B/m³ with an uncertainty factor (UF) of 40. Sensory irritation was considered to be the most sensitive effect for the portal of entry. An OEL of 1.4 mg B/m³ was estimated for this effect based on the identified POD and an UF of 1. An OEL of 1.4 mg B/m³ as an 8-h time-weighted average (TWA) is recommended.     

Urinary metabolites as biomarkers of human exposure to atrazine: atrazine mercapturate in agricultural workers

Human exposure to atrazine and other triazine herbicides results in urinary excretion of traces of parent compounds and of their metabolites formed by N-dealkylation or conjugation with mercapturic acid. In contrast to N-dealkylated metabolites, which are not compound-specific, the measurement of atrazine mercapturate and unchanged atrazine provides an unambiguous confirmation of exposure to this herbicide. The aim of this study was to investigate the levels of these two compounds in a group of agricultural workers who may be considered representative for typical behaviour and procedures during the atrazine application in Croatia. The spot urine samples were collected at the beginning (samples A) and at the end (samples B) of a working day and 12h after exposure has ended (samples C). Atrazine and atrazine mercapturate were extracted from acidified urine samples (pH 2) with ethyl acetate and the extracts were analysed using high performance liquid chromatography-tandem mass spectrometry with a turbo ion spray (electrospray) ionization interface. The detection limits based on treatment of 2ml urine samples were 0.2ngml(-1) for both analytes. Atrazine was not detected in any of 27 analysed urine samples but traces of atrazine mercapturate were measured in about a third of pre-exposure and in all post-exposure urine samples in mass concentrations ranging from 0.3 to 10.4ngml(-1) (0.3 to 8.0μgg(-1) of creatinine). The metabolite concentrations in B and C group of post-exposure samples were not significantly different. The urinary atrazine mercapturate post-exposure concentrations were comparable to those reported for U.S. farmers engaged in a single field application of atrazine.     

Endpoints and surrogates for use in population studies in toxicology

Risk characterisation of human exposure to chemicals requires information on the intrinsic toxic (hazardous) properties of the chemical, dose response of effects for the critical endpoints and exposure of the population. Information on hazardous properties, including data on mechanism and toxicokinetics, is necessary to define the critical endpoints and the relevant parameters to assess internal exposure and its relation to external exposure. Consequently the design of population studies to evaluate toxic effects or to monitor exposed cohorts must consider the critical endpoints of toxic effects and exposure. External exposure is determined by chemical analysis of the chemicals in food, water or air. The more relevant internal exposure is assessed by analysis of the chemical or its metabolites in body fluids and, if appropriate, by protein- or DNA-adducts. Effects are monitored by determining the relevant organ-specific parameters. In the case of genotoxic agents, effect biomonitoring parameters, like cytogenetic effects in peripheral blood cells or DNA strand breaks, are applied. Genotyping to detect deficiencies in the expression of enzymes, e.g. those involved in metabolic activation or inactivation, may explain interindividual differences in susceptibility. Overall prospective population studies allow exposure monitoring and risk assessment of human exposure only when such parameters are included.     

Occurrence and exposure assessment of aflatoxins in Zhejiang province,China

The purpose of this study was to assess the risk of aflatoxins due to multiple food consumption among the Zhejiang population. Ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method was used to determine aflatoxins in 792 samples. Aflatoxins were detected in 27.1% of the samples at levels between 0.07 and 262.63 μg kg⁻¹, and aflatoxins B₁ was the most frequently detected among different types of samples. 0.8% of peanut oil, 3.39% of nut products as well as 1.1% of condiments contaminated with aflatoxins B₁ exceeded China national tolerance limits. Peanut oil had the highest incidence of aflatoxin, with a range from 0.17 to 22.50 μg kg⁻¹. Using bags conferred limited advantages in reducing aflatoxin contents. Moreover, peanut and rice were the main contributors to dietary exposure to aflatoxins among Zhejiang residents. Finally, the margin of exposure values obtained by rice consumption were far from the safe margin of 10,000, indicating a potential risk to public health. The results pointed out the need for further prioritization of aflatoxins B₁ risk-management actions in Zhejiang.     

Urinary acrylamide metabolites as biomarkers for short-term dietary exposure to acrylamide.

It has previously been reported that heat-treated carbohydrate rich foods may contain high levels of acrylamide resulting in consumers being inadvertently exposed to acrylamide. Acrylamide is mainly excreted in the urine as mercapturic acid derivatives of acrylamide and glycidamide. In a clinical study comprising of 53 subjects, the urinary excretion of these metabolites was determined using solid-phase extraction and liquid chromatography with positive electrospray MS/MS detection. The median (range) total excretion of acrylamide in urine during 24 h was 16 (7-47) microg acrylamide for non-smokers and 74 (38-106) microg acrylamide for smokers, respectively. It was found that the median intake estimate in the study based on 24 h dietary recall was 21 (13-178) and 26 (12-67) for non-smokers and smokers, respectively. The median dietary exposure to acrylamide was estimated to be 0.47 (range 0.17-1.16) microg/kg body weight per day. In a multiple linear regression analysis, the urinary excretion of acrylamide metabolites correlated statistically significant with intake of aspartic acid, protein, starch and coffee. Consumption of citrus fruits correlated negatively with excretion of acrylamide metabolites.     

手术室骨科专科护士职业暴露的风险管理与防护

目的探讨手术室骨科专科护士职业暴露的风险管理与防护。方法采集2009年1月-2009年125480例骨科关节置换手术护士职业暴露的例数,进行风险因素评估,制定护理对策,预警干预手术室护士职业暴露的发生。结果通过对480例骨科关节置换手术骨科专科护士职业暴露发生例数分析,其中对照组发生职业暴露22例,职业暴露发生率为8．8％;干预组5例,职业暴露发生率为2．2％,两组间的差异有统计学意义（P〈0．01）。结论通过风险因素评估,干预手术室护士职业暴露的发生,降低手术护士职业暴露发生率。     

The relationship between nicotine dependence scores and biomarkers of exposure in adult cigarette smokers

Background: Tobacco dependence is a multidimensional phenomenon. The Fagerström Test for Nicotine Dependence (FTND) is a widely administered six-item questionnaire used as a measure of nicotine dependence. It has been suggested that this test may not represent the entire spectrum of factors related to dependence. Also the relationship of this test with biomarkers of exposure to cigarette smoke has not been extensively studied. Methods: Data from a multi-center, cross-sectional, ambulatory study of US adult smokers (the Total Exposure Study, TES) was analyzed. The FTND score and a number of additional questions related to smoking behavior, from an adult smoker questionnaire (ASQ) completed by 3585 adult smokers in the TES were analyzed. The 24-h urine nicotine equivalents, serum cotinine and blood carboxyhemoglobin were measured as biomarkers of exposure (BOE) to nicotine and carbon monoxide. Cigarette butts returned were collected during the 24-h urine collection period. Results: The FTND showed moderate correlations with BOE, while selected questions from ASQ although statistically significant, had weaker correlations. FTND scores showed substantially weaker correlations without the question about cigarettes smoked per day (CPD). CPD and time to first cigarette (TTFC) had the most impact on BOE. Conclusion: Additional questions from ASQ did not appear to contribute towards refining the FTND test. The correlation of the FTND scores with nicotine and carbon monoxide seems to be primarily driven by CPD. CPD and TTFC were the most important factors correlating with exposure.     

Comparison of human health risks resulting from exposure to fungicides and mycotoxins via food

The interest in holistic considerations in the area of food safety is increasing. Risk managers may face the problem that reducing the risk of one compound may increase the risk of another compound. An example is the potential increase in mycotoxin levels due to a reduced use of fungicides in crop production. The Integrated Probabilistic Risk Assessment (IPRA) model was used to compare the estimated health impacts on humans caused by crops contaminated with the fungicides spiroxamine (SPI) and tebuconazole (TEB) or with the mycotoxins deoxynivalenol (DON) and zearalenone (ZEA). The IPRA model integrates a distribution characterising the exposure of individuals with a distribution characterising the susceptibility of individuals towards toxic effects. Its outcome, a distribution of Individual Margins of Exposure (IMoE), served as basis to perform comparisons of compounds, effects, countries, and population groups. Based on the available data and the assumptions made, none of the four compounds was found to have impact on human health in the addressed scenarios. The IMoE distributions were located as follows: DON < TEB = ZEA < SPI, showing DON to be the compound with the highest potential for negative health impacts. The presented approach can help risk managers to prioritise risk-reduction measures.     

Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide

An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data-driven alternative approach to managing the potential risks from exogenous exposures to EO.     

Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures

Human exposure to bisphenol A is controversially discussed. This review critically assesses methods for biomonitoring of bisphenol A exposures and reported concentrations of bisphenol A in blood and urine of non-occupationally ("environmentally") exposed humans. From the many methods published to assess bisphenol A concentrations in biological media, mass spectrometry-based methods are considered most appropriate due to high sensitivity, selectivity and precision. In human blood, based on the known toxicokinetics of bisphenol A in humans, the expected very low concentrations of bisphenol A due to rapid biotransformation and the very rapid excretion result in severe limitations in the use of reported blood levels of bisphenol A for exposure assessment. Due to the rapid and complete excretion of orally administered bisphenol A, urine samples are considered as the appropriate body fluid for bisphenol A exposure assessment. In urine samples from several cohorts, bisphenol A (as glucuronide) was present in average concentrations in the range of 1-3 microg/L suggesting that daily human exposure to bisphenol A is below 6 microg per person (<0.1 microg/kg bw/day) for the majority of the population.     

The role of exposure reconstruction in occupational human health risk assessment: Current methods and a recommended framework

Exposure reconstruction for substances of interest to human health is a process that has been used, with various levels of sophistication, as far back as the 1930s. The importance of robust and high-quality exposure reconstruction has been recognized by many researchers. It has been noted that misclassification of reconstructed exposures is relatively common and can result in potentially significant effects on the conclusions of a human health risk assessment or epidemiology study. In this analysis, a review of the key exposure reconstruction approaches described in over 400 papers in the peer-reviewed literature is presented. These approaches have been critically evaluated and classified according to quantitative, semiquantitative, and qualitative approaches. Our analysis indicates that much can still be done to improve the overall quality and consistency of exposure reconstructions and that a systematic framework would help to standardize the exposure reconstruction process in the future. The seven recommended steps in the exposure reconstruction process include identifying the goals of the reconstruction, organizing and ranking the available data, identifying key data gaps, selecting the best information sources and methodology for the reconstruction, incorporating probabilistic methods into the reconstruction, conducting an uncertainty analysis, and validating the results of the reconstruction. Influential emerging techniques, such as Bayesian data analysis, are highlighted. Important issues that will likely influence the conduct of exposure reconstruction into the future include improving statistical analysis methods, addressing the issue of chemical mixtures, evaluating aggregate exposures, and ensuring transparency with respect to variability and uncertainty in the reconstruction effort.     

Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic

Human exposure to environmental chemicals is most correctly characterized as exposure to mixtures of these agents. The metals/metalloids, lead (Pb), cadmium (Cd), and arsenic (As), are among the leading toxic agents detected in the environment. Exposure to these elements, particularly at chronic low dose levels, is still a major public health concern. Concurrent exposure to Pb, Cd, or As may produce additive or synergistic interactions or even new effects that are not seen in single component exposures. Evaluating these interactions on a mechanistic basis is essential for risk assessment and management of metal/metalloid mixtures. This paper will review a number of individual studies that addressed interactions of these metals/metalloids in both experimental and human exposure studies with particular emphasis on biomarkers. In general, co-exposure to metal/metalloid mixtures produced more severe effects at both relatively high dose and low dose levels in a biomarker-specific manner. These effects were found to be mediated by dose, duration of exposure and genetic factors. While traditional endpoints, such as morphological changes and biochemical parameters for target organ toxicity, were effective measures for evaluating the toxicity of high dose metal/metalloid mixtures, biomarkers for oxidative stress, altered heme biosynthesis parameters, and stress proteins showed clear responses in evaluating toxicity of low dose metal/metalloid mixtures. Metallothionein, heat shock proteins, and glutathione are involved in regulating interactive effects of metal/metalloid mixtures at low dose levels. These findings suggest that further studies on interactions of these metal/metalloid mixtures utilizing biomarker endpoints are highly warranted.     

Occupational exposure limits for manufactured nanomaterials,a systematic review

Background: The toxicological properties of manufactured nanomaterials (MNMs) can be different from their bulk-material and uncertainty remains about the adverse health effects they may have on humans. Proposals for OELs have been put forward which can be useful for risk management and workers’ protection. We performed a systematic review of proposals for OELs for MNMs to better understand the extent of such proposals, as well as their derivation methods.

Methods: We searched PubMed and Embase with an extensive search string and also assessed the references in the included studies. Two authors extracted the data independently.

Results: We identified 20 studies that proposed in total 56 OEL values. Of these, two proposed a generic level for all MNMs, 14 proposed a generic OEL for a category of MNMs and 40 proposed an OEL for a specific nanomaterial. For specific fibers, four studies proposed a similar value but for carbon nanotubes (CNTs) the values differed with a factor ranging from 30 to 50 and for metals with a factor from 100 to 300. The studies did not provide explanations for this variation. We found that exposure to MNMs measured at selected workplaces may exceed even the highest proposed OEL. This indicates that the application and use of OELs may be useful for exposure reduction.

Conclusion: OELs can provide a valuable reference point for exposure reduction measures in workplaces. There is a need for more and better supported OELs based on a more systematic approach to OEL derivation.     

Human health risk assessment of endosulfan: II. Dietary exposure assessment

The California Department of Pesticide Regulation (CDPR) and the United States Environmental Protection Agency (USEPA) performed dietary exposure assessments for endosulfan in 1998 and 2002, respectively. Results of the USEPA assessment showed an increased risk for the population sub-group “Children 1–6 years” (>100% of the Population Adjusted Dose [PAD]). USEPA then required registrants to satisfy database uncertainties by performing subchronic neurotoxicity and developmental neurotoxicity studies and, based on the results, USEPA decreased the Food Quality Protection Act (FQPA, 1996) Safety Factor from 10× to 1×. Additionally, several tolerances on commodities consumed in quantity by children were cancelled in 2006. CDPR re-evaluated the dietary risk initially performed in 1998 after review of these same studies. Based on a review of the revised USEPA tolerances, decreased usage, decreased consumption, cancellations, and prior health protective margins of exposure (MOEs > 100), CDPR determined that it was not necessary to redo the 1998 exposure assessment. In 2007, USEPA conducted a new human health risk assessment for endosulfan combining food + drinking water residues that characterized dietary risk as %PAD = ([Exposure ÷ PAD] × 100). For all relevant USEPA population sub-groups, the %PADs were < 100% (health protective benchmark).     

Background, approaches and recent trends for setting health-based occupational exposure limits: a minireview

The setting of occupational exposure limits (OELs) are founded in occupational medicine and the predictive toxicological testing, resulting in exposure-response relationships. For compounds where a No-Observed-Adverse-Effect-Level (NOAEL) can be established, health-based OELs are set by dividing the NOAEL of the critical effect by an overall uncertainty factor. Possibly, the approach may also be used for carcinogens if the mechanism is epigenetic or the genetic effect is secondary to effect from reactions with proteins such as topoisomerase inhibitors, and mitotic and meiotic spindle poisons. Additionally, the NOAEL approach may also be used for compounds with weak genotoxic effect, playing no or only a minor role in the development of tumours. No health-based OEL can be set for direct-acting genotoxic compounds where the life-time risks may be estimated from the low-dose linear non-threshold extrapolation, allowing a politically based exposure level to be set. OELs are set by several agencies in the US and Europe, but also in-house in major chemical and pharmaceutical companies. The benchmark dose approach may in the future be used where it has advantage over the NOAEL approach. Also, more attention should be devoted to sensitive groups, toxicological mechanisms and interactions as most workplace exposures are mixtures.     

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure

Introduction

Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen).

Materials and methods

We assessed the accuracy of the models’ predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1 h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated.

Results

With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52–4.19 mg/L with the Bos model, 1.42–4.04 mg/L with the Mumtaz model, and 1.81–4.31 mg/L with the Jongeneelen model compared to 0.27–5.44 mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4–2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels.

Conclusions

The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.     

Using exposure bands for rapid decision making in the RISK21 tiered exposure assessment

The ILSI Health and Environmental Sciences Institute (HESI) Risk Assessment in the Twenty-first Century (RISK21) project was initiated to address and catalyze improvements in human health risk assessment. RISK21 is a problem formulation-based conceptual roadmap and risk matrix visualization tool, facilitating transparent evaluation of both hazard and exposure components. The RISK21 roadmap is exposure-driven, that is, exposure is used as the second step (after problem formulation) to define and focus the assessment. This paper describes the exposure tiers of the RISK21 matrix and the approaches to adapt readily available information to more quickly inform exposure at a screening level. In particular, exposure look-up tables were developed from available exposure tools (European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) for worker exposure, ECETOC TRA, European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) for consumer exposure, and USEtox^® for indirect exposure to humans via the environment) and were tested in a hypothetical mosquito bed netting case study. A detailed WHO risk assessment for a similar mosquito net use served as a benchmark for the performance of the RISK21 approach. The case study demonstrated that the screening methodologies provided suitable conservative exposure estimates for risk assessment. The results of this effort showed that the RISK21 approach is useful for defining future assessment efforts, focusing assessment activities and visualizing results.