Experimental Human Exposure Research Articles

Mechanisms of Immune Dysregulation Induced by Pesticide Exposure and their Implications for Cancer: A Systematic Review

The inappropriate use of pesticides contaminates natural resources and has consequences for human health. Evidence of immune dysregulation caused by pesticides has been presented, but studies linking exposure to these substances with immune dysregulation and its relationship to cancer are scarce. This study systematically reviews the published literature that addresses the topic of immune dysregulation and cancer and its relationship to pesticide exposure. Studies developed in vitro cell culture and in vivo experimental animals and human exposure data were included. The results show that pesticide exposure has a relevant impact on immune dysfunction, negatively affecting immune system cells and cytokine production in innate and adaptive responses. The main consequences reported were suppression of the Th1 response, induction of the Th2 response, cellular balance dysregulation, and cytokine production changes. All reported events are related to the occurrence of immunosuppression. This dysregulation is paramount for cancer progression and may lead to a worse prognosis in chronically exposed populations. These findings also point to the need for further studies, primarily focused on human exposure.

Iron content in aerosol particles and its impact on atmospheric chemistry.

Atmospheric aerosol effects on ecological and human health remain uncertain due to their highly complex and evolving nature when suspended in air. Atmospheric chemistry, global climate/oceanic and health exposure models need to incorporate more realistic representations of aerosol particles, especially their bulk and surface chemistry, to account for the evolution in aerosol physicochemical properties with time. (Photo)chemistry driven by iron (Fe) in atmospheric aerosol particles from natural and anthropogenic sources remains limited in these models, particularly under aerosol liquid water conditions. In this feature article, recent advances from our work on Fe (photo)reactivity in multicomponent aerosol systems are highlighted. More specifically, reactions of soluble Fe with aqueous extracts of biomass burning organic aerosols and proxies of humic like substances leading to brown carbon formation are presented. Some of these reactions produced nitrogen-containing gaseous and condensed phase products. For comparison, results from these bulk aqueous phase chemical studies were compared to those from heterogeneous reactions simulating atmospheric aging of Fe-containing reference materials. These materials include Arizona test dust (AZTD) and combustion fly ash particles. Also, dissolution of Fe and other trace elements is presented from simulated human exposure experiments to highlight the impact of aerosol aging on levels of trace metals. The impacts of these chemical reactions on aerosol optical, hygroscopic and morphological properties are also emphasized in light of their importance to aerosol-radiation and aerosol-cloud interactions, in addition to biogeochemical processes at the sea/ocean surface microlayer upon deposition. Future directions for laboratory studies on Fe-driven multiphase chemistry are proposed to advance knowledge and encourage collaborations for efficient utilization of expertise and resources among climate, ocean and health scientific communities.

Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust

Experimental human exposure studies are an effective tool to study adverse health effects from acute inhalation of particulate matter and other constituents of air pollution. In this randomized and double-blinded crossover study, we investigated the systemic effect on bioactive lipid metabolite levels after controlled biodiesel exhaust exposure of healthy humans and compared it to filtered air at a separate exposure occasion. Eicosanoids and other oxylipins, as well as endocannabinoids and related lipids, were quantified in plasma from 14 healthy volunteers at baseline and at three subsequent time points (2, 6, and 24 h) after 1 h exposure sessions. Protocols based on liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) methods were developed to detect temporal changes in circulating levels after biodiesel exhaust exposure. The exhaust was generated by a diesel engine fed with an undiluted rapeseed methyl ester fuel. Among the 51 analyzed lipid metabolites, PGF2α, 9,10-DiHOME, 9-HODE, 5-HETE, 11-HETE, 12-HETE, and DEA displayed significant responsiveness to the biodiesel exhaust exposure as opposed to filtered air. Of these, 9-HODE and 5-HETE at 24 h survived the 10% false discovery rate cutoff (p < 0.003). Hence, the majority of the responsive lipid metabolites were monohydroxy fatty acids. We conclude that it is possible to detect alterations in circulating bioactive lipid metabolites in response to biodiesel exhaust exposure using LC-MS/MS, with emphasis on metabolites with inflammation related properties and implications on cardiovascular health and disease. These observations aid future investigations on air pollution effects, especially with regard to cardiovascular outcomes.

Interplay of air pollution and asthma immunopathogenesis: a focused review of diesel exhaust and ozone.

Controlled human exposure experiments with diesel exhaust particles (DEPs) and ozone serve to illustrate the important role pollutants play in modulating both allergic mechanisms and immune responses to affect the immunopathogenesis of airway diseases such as asthma. For DEP, evidence is stronger for the exacerbation of existing asthma rather than for the development of new disease. To the extent that this enhancement occurs, the augmentation of Th2-type immunity seems to be a common element. For ozone, neutrophilic inflammation, altered immune cell phenotype and function and oxidative stress are all marked responses that likely contribute to underlying immune-inflammatory features of asthma. Evidence is also emerging that unique gene signatures and epigenetic control of immune and inflammatory-based genes are playing important roles in the magnitude of the impact ozone is having on respiratory health. Indeed, the interplay between air pollutants such as DEP and ozone and asthma immunopathogenesis is an ongoing concern in terms of understanding how exposure to these agents can lead to worsening of disease. To this end, asthmatics may be pre-disposed to the deleterious effects of pollutants like ozone, having constitutively modified host defense functions and gene signatures. Although this review has utilized DEP and ozone as example pollutants, more research is needed to better understand the interplay between air pollution in general and asthma immumopathogenesis.

Update in environmental and occupational lung diseases 2013.

In this update, recent publications within the field of environmental and occupational medicine, from this journal and others, are highlighted. Effects of ambient air pollution on a diverse range of airways disease continue to be discovered, reiterating the impressive potency of this near-ubiquitous and largely anthropogenic toxicant. Air pollution is now recognized as the third leading cause of disability-adjusted life years due to chronic respiratory disease globally (1). Studies in the past year have significantly strengthened the link between air pollution exposure and adverse health outcomes including mortality (2–4), lung cancer (4–6), infections (7–9), and obstructive lung disease (including asthma) (10, 11). Important underlying mechanistic details were illuminated in several animal models (12–17). The association between poor indoor air quality and lung diseases is a topic of increasing interest and was investigated in several reports in 2013 (18–21). Controlled human exposure experiments were in the spotlight, in part because of ethical concerns about the justification of this approach. An important position paper by leading researchers and a biomedical ethicist strongly supports the usefulness of controlled exposures, which continue to provide new insights into adverse health effects of different pollutants (22). Asbestos exposure is a well-recognized risk factor for pleural mesothelioma, and two epidemiology studies were published that explored the interaction between exposure to asbestos, other mineral fibers, and cigarette smoking in mesothelioma, asbestosis, and lung cancer (23, 24). Arsenic is increasingly recognized as a groundwater contaminant, with potential effects on lung development and function. An important paper provided strong evidence that even low levels of arsenic exposure are associated with reduced lung function (25). The adverse health effects of global warming are becoming apparent, and one paper provided a sobering reminder that elevated ambient temperatures are a strong risk factor for respiratory morbidity (26). Unfortunately, the adverse effects of environmental and occupational exposures on lung health occur disproportionately in ethnic minorities and those with lower socioeconomic status, underscoring the urgent need to address these important health disparities (27). Although our understanding of the adverse effects of environmental and occupational exposures on lung health continues to expand, more research is needed to understand mechanisms involved and discover the optimal public health measures to mitigate risk.

Air pollution and health

The detrimental health effects of air pollution have always attracted intense interest among researchers from around the world. In 2010, WHO estimated that more than 6 million people die prematurely every year because of air pollution. 1 Lim SS Vos T Flaxman AD et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380: 2224-2260 Summary Full Text Full Text PDF PubMed Scopus (8390) Google Scholar Both ambient air pollution and indoor air pollution have been linked to various adverse health outcomes, especially in people with pre-existing medical conditions. Although it might seem obvious that air pollution can affect people with pre-existing airway diseases, there are few controlled human exposure studies that can provide irrefutable evidence of adverse effects after acute exposure to an individual pollutant. 2 Brunekreef B Holgate ST Air pollution and health. Lancet. 2002; 360: 1233-1242 Summary Full Text Full Text PDF PubMed Scopus (2957) Google Scholar Such controlled human exposure studies might also enable a better understanding of the underlying mechanisms leading to possible adverse outcomes. 3 Rom WN Boushey H Caplan A Experimental human exposure to air pollutants is essential to understand adverse health effects. Am J Respir Cell Mol Biol. 2013; 49: 691-696 Crossref PubMed Scopus (22) Google Scholar Ambient air contains many pollutants including gases such as ozone, oxides of nitrogen, and sulphur dioxide along with particulates of different sizes. Because of the complexity of the composition of air pollutants and the difficulty of precisely measuring exposure, identifying the role of different pollutants in respiratory morbidity is no simple task. Quantification of pollutant exposure in a study population is imprecise, because the levels of different components might vary with time and with the surroundings of the studied participants. Despite these difficulties, there have been several important reports published in 2013 that improve our understanding of the adverse health effects of air pollution.

Experimental Human Exposure to Air Pollutants Is Essential to Understand Adverse Health Effects

Air pollution has been found to cause significant global mortality, with 6.8 million excess deaths attributed to air pollution each year, and similarly large numbers of exacerbations of asthma, chronic obstructive pulmonary disease, and cardiovascular diseases. Epidemiological research has identified associations, and experimental human exposure has provided critical information on dose-response relationships of adverse effects caused by controlled human exposure to individual pollutants. Human exposures further enable examination of the relationship of adverse effects such as symptoms and pulmonary function changes to presumed mechanisms of disease revealed through analysis of bronchoalveolar lavage fluid obtained from the lower respiratory tract. In this Perspective, we analyze the ethics of human exposure, the importance of the information gained, and the risks of such exposure. We find that these studies appear to have been done with proper approval of institutional review boards, were done with informed consent from the participants, and have rarely been associated with serious adverse events.

DNA Hypomethylation, Ambient Particulate Matter, and Increased Blood Pressure: Findings From Controlled Human Exposure Experiments

BackgroundShort‐term exposures to fine (<2.5 μm aerodynamic diameter) ambient particulate‐matter (PM) have been related with increased blood pressure (BP) in controlled‐human exposure and community‐based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM, hypomethylation, and BP.Methods and ResultsWe conducted a cross‐over trial of controlled‐human exposure to concentrated ambient particles (CAPs). Fifteen healthy adult participants were exposed for 130 minutes to fine CAPs, coarse CAPs, or HEPA‐filtered medical air (control) in randomized order with ≥2‐week washout. Repetitive‐element (Alu, long interspersed nuclear element‐1 [LINE‐1]) and candidate‐gene (TLR4, IL‐12, IL‐6, iNOS) blood methylation, systolic and diastolic BP were measured pre‐ and postexposure. After adjustment for multiple comparisons, fine CAPs exposure lowered Alu methylation (β‐standardized=−0.74, adjusted‐P=0.03); coarse CAPs exposure lowered TLR4 methylation (β‐standardized=−0.27, adjusted‐P=0.04). Both fine and coarse CAPs determined significantly increased systolic BP (β=2.53 mm Hg, P=0.001; β=1.56 mm Hg, P=0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P=0.12; β=0.82 mm Hg, P=0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β‐standardized=0.41, P=0.04; and β‐standardized=0.84, P=0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β‐standardized=1.45, P=0.01).ConclusionsOur findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM. Our results provide the first experimental evidence of PM‐induced DNA hypomethylation and its correlation to BP.

Use of a Human Influenza Challenge Model to Assess Person-to-Person Transmission: Proof-of-Concept Study

Influenza transmission in humans remains poorly understood. In particular, the relative contribution of contact, large droplet, and aerosol transmission is unknown. The aims of this proof-of-concept study were to determine whether an experimentally induced influenza infection is transmissible between humans and whether this would form a viable platform for future studies. In a quarantine facility, healthy volunteers ("donors") were inoculated with A/Wisconsin/67/2005 (H3N2) influenza virus via intranasal drops. On study days 2 and 3 "recipient" volunteers were exposed to donors under close living conditions. Volunteers socialized for 30 hours during a 2-day period. Infection was confirmed by ≥1 positive results from polymerase chain reaction, virus culture, or serology. After inoculation, 4 of 9 donors developed symptoms consistent an influenza-like illness (ILI) and 7 of 9 were proven to be influenza-infected. After exposure, 4 of 15 recipients developed symptoms of ILI and 3 of 15 were proven to be infected. Serum collected within 2 days of study initiation indicated that 1 donor and 3 recipients were seropositive at study initiation. After adjustment for preexposure immunity, the overall secondary attack rate was 25% (3 of 12). Experimental human exposure studies offer an attractive potential method for answering outstanding questions related to influenza transmission and the evaluation of interventions to reduce it.

Current Status of the Toxicology of Diesel Engine Exhaust — and the ACES Project

A clear understanding of the health risks of DE has been elusive, because exposures of the workers and general populations studied epidemiologically have not been accurately measured. Experimental exposures of humans and animals can be measured and these have suggested potential health hazards, but results of experimental exposures have been difficult to place in a realistic human exposure context. Experimental human exposures must be of only short duration and relatively high concentrations of DE have been necessary to produce short-term effects. Short-term and long-term animal studies have been conducted and significant progressive health effects have been produced at extreme exposure concentrations, but it is difficult to translate those results into risk factors for humans with acceptable confidence. Diesel technologies have advanced markedly over the past few decades, and emissions have been reduced and altered in composition. No published epidemiological or toxicological study has used exhaust produced by recent diesel technologies. The ACES program in the United States was created to conduct animal studies of the potential health hazards of recent technology diesel exhaust. Rats and mice are exposed to different dilutions of exhaust from a heavy-duty engine meeting the 2007 on-road emission standards and operated on a variable-duty cycle. The study is underway and early results will be available in early 2011. Final results from the long-term study of the hazards of cancer and progressive non-cancer disease will be available in late 2013.

Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment.

Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde-exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta-analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde-induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde-DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia.

Excretion of unchanged volatile organic compounds (toluene, ethylbenzene, xylene and mesitylene) in urine as result of experimental human volunteer exposure

To investigate elimination of unchanged volatile organic compounds (VOC's) through urine and the use of respective data for occupational exposure assessment, six volunteers were exposed under controlled conditions to toluene (TOL), ethylbenzene (EB), xylene (XYL) and mesitylene (MES) at concentrations ranging from 20 to 200 mg/m(3). The study was to elicit the toxicokinetic data and compare the precision of VOC's exposure assessment based on determining unchanged compounds in blood, urine and their metabolites in urine. During and after exposure blood and urine samples were analysed by gas chromatography using the headspace and SPME headspace technique The kinetics of VOC's elimination in urine complied with an open two-compartment model. The (half-time) T (1/2 )values varied from 0.45 to 0.88 h for phase I and from 6.7 to 19.2 h for phase II. The precision of the method for unchanged VOC's was similar to that based on unchanged compounds in blood and better than their main metabolites in urine. The obtained result indicate that determining unchanged VOC's in urine can be used as an exposure test even in the ranges of VOC's in the air that are much lower than the current TWA for occupational exposure.

The use of Markov chain Monte Carlo uncertainty analysis to support a Public Health Goal for perchloroethylene

The current Public Health Goal (PHG) for perchloroethylene (PCE) was derived using upper-bound estimates of fractional PCE metabolism in humans. These estimates were in part obtained from a published evaluation of the uncertainty and variability in human PCE metabolism conducted using a physiologically-based pharmacokinetic (PBPK) model in a Markov chain Monte Carlo (MCMC) analysis; however, the data used in that analysis were limited to post-exposure PCE blood and exhaled air concentrations from a single study. A more recent study [Volkel, W., Friedewald, M., Lederer, E., Pahler, A., Parker, J., Dekant, W., 1998. Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl- S-(trichlorovinyl)- l-cysteine in rats and humans after inhalation. Toxicol. Appl. Pharmacol. 153(1), 20–27.] provides data on blood concentrations of PCE and its major metabolite, trichloroacetic acid (TCA), and urinary excretion of TCA following exposure of human subjects to lower concentrations of PCE (10–40 ppm) than in previous studies. In the present effort, a new MCMC analysis was performed that focused on data from this study along with two others [Fernandez, J., Guberan, E., Caperos, J., 1976. Experimental human exposures to tetrachloroethylene vapor and elimination in breath after inhalation. Am. Ind. Hyg. Assoc. J. 37, 143–150; Monster, A., Boersma, G., Steenweg, H., 1979. Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load. Int. Arch. Occup. Environ. Health 42, 303–309.] providing data on PCE blood concentrations and urinary excretion of TCA. To provide an accurate prediction of TCA kinetics, the PBPK model used here includes a description of the metabolism of PCE to TCA in both the liver and kidney. The resulting upper 95th percentile estimates of fraction of PCE metabolized by inhalation and oral routes were 2.1 and 5.2%, respectively, compared to 58 and 79% used in the derivation of the PHG.

Biological monitoring of experimental human exposure to hydrocarbon solvent mixtures

The aim of the study was to develop and to validate a suitable analytical method in order to assess the internal exposure of persons to commercial products of hydrocarbon solvent mixtures (HSM). Twenty healthy volunteers were exposed to vapours of five commercial HSM for 8 h at 200–1000 mg/m 3 air. Aromatic-rich, aromatic-poor and aromatic-free HSM were used, as well as isohexane and technical hexane mixtures. A total of 300 exposures were carried out at rest or with an exercise period of 10 min/h at 50 and 75 W. Blood samples for the determination of the HSM were collected before and immediately after exposure. They were analyzed with a headspace analyzer by gas chromatography and mass spectrometry. The analytical method has detection limits of 2–50 μg HSM/L blood. With this method we obtained intra- and interassay variation coefficients of 3.7–15.1%, at concentrations of 53–1500 μg HSM/L blood. The mean values of the HSM of the 20 volunteers after 8 h range between 89 μg/L (technical hexane-mixture) and 1369 μg/L blood (aromatic-free HSM) at rest. Physical exercises of 50 and 75 W, respectively, lead to a significant increase of the blood-concentrations by mean factors between 1.2 and 1.9 for the five HSM. In conclusion, our results demonstrate that physical activity should be considered in the setting of occupational exposure limits.

Human Exposure Chamber for Known Formaldehyde Levels: Generation and Validation

Formaldehyde is a common air pollutant of the indoor environment. It has a potential effect on the respiratory function of people and so studies have been performed to assess this using exposure methods with high concentrations of formaldehyde. However, epidemiology studies have shown its impact on allergic diseases at lower domestic levels. The aim of this study was to develop an exposure chamber to study effects of low controlled concentrations of formaldehyde. Concentrations in the chamber were quantified by a simple DNHP-derivatisation method followed by liquid chromatography coupled to UV detection. Experiments to assess formaldehyde generation yield and reproducibility of formaldehyde levels in the chamber were performed in an empty chamber. The temporal decay of formaldehyde concentration in the exposure chamber was also investigated for more than 2h under different experimental conditions, for example in darkness or with somebody inside the chamber. Actual measured levels of formaldehyde were found to be 78-91% of the calculated value expected. The study of the temporal decay showed that subject’s breathing accounted for the fate of approximately 50% of the formaldehyde lost. Leaks, wall deposition, photolysis and adsorption on clothes were processes identified to explain the remaining 50%. However, this study has shown that both homogeneity and stability of formaldehyde concentration in the gas phase can be maintained acceptably to carry out future human exposure experiments.

Biological effects of Utah Valley ambient air particles in humans: a review.

The Utah Valley provided a unique opportunity to evaluate the health effects of particulate matter (PM) in humans. The area has had intermittently high particle levels with the principal point source being a steel mill. Due to a labor dispute, the mill was shut down. The closure and reopening of the steel mill allowed for an examination of potential correlates between epidemiological observations and measures of the biological effect of PM with experimental cell and human exposure. Epidemiologic investigation demonstrated an association of both the closure of the steel mill and the reduction in exposure to air pollution particles with changes in morbidity and mortality. Changes in these parameters were not fully accounted for by variation in the mass of PM. Metal content, in vitro oxidative stress, and release of pro-inflammatory mediators by cultured respiratory epithelial cells were all elevated in those aqueous extracts collected from the Utah Valley while the steel mill was open. Similarly, inflammatory injury in the lower respiratory tract of humans after instillation of aqueous extracts of filter PM was increased in those volunteers exposed to particles collected while the mill was open. These results indicate that equal masses of PM can induce disparate lung injuries suggesting that particle components may be relevant in assessing health effects after their exposure. Specifically, metals can participate in the biological effects of PM collected from the Utah Valley. In addition, correlates between findings of epidemiological studies and the biological effects of PM in cell and human investigation were demonstrated.

The Ethics of Using Human Panels in the Indoor Air Sciences

The Helsinki Declaration and similar national regulations require that the ethical aspects of all intended experimental exposures of humans should be evaluated and found acceptable, using the best available toxicological principles and data. In the low-level exposure ranges of indoor air, very little is known about the principles for such evaluations and few health data exist. This paper discusses principles for such evaluations in relation to experimental exposures of IAQ panels. The acceptability of chemical exposures of human subjects in IAQ research should be based on the following principles, a) Only reversible non-adverse health effects can be accepted. The risk of adverse effects associated with exposure must be documented to be acceptably low. b) Exposures to well-known chemicals or emissions from commercially available sources can be accepted if these sources have a history of many years' problem-free use on the free market and if their use during the experimental exposures corresponds to normally encountered exposures. Studies including exceptional exposures or sensitive subjects should be registered and evaluated by the local ethics committees. c) Exposures to emissions from new types of source can be accepted if the exposures are chemically identified and are below official indoor, outdoor or occupational guidelines for exposures. Procedures for the evaluation of exposures to compounds lacking toxicological data are discussed. These exposures should be registered and evaluated by local ethics committees. d) The selection of subjects must include special pre-tests and defined exclusion criteria to exclude risk groups.

Experimental human exposure to N,N-dimethylbenzylamine: generation of a controlled atmosphere and biological monitoring.

The aim of the present study was to develop a method for generation of dimethylbenzylamine (DMBA) atmospheres in an exposure chamber and to investigate the possibility of using urinary DMBA metabolites for biological monitoring of exposure to DMBA. A DMBA atmosphere was generated by use of the gas-permeation principle. Six health male volunteers were exposed for 8 h to DMBA at air levels of 20, 45, and 80 microns/m3. Air levels of DMBA were analyzed by gas chromatography (GC). The total urinary amount of DMBA (U-SumDMBA; DMBA and metabolites that can be reduced to DMBA, e.g., DMBAO) was analyzed using GC-mass spectrometry (MS). The exposure chamber maintained very low (0-130 micrograms/m3) and steady concentrations for several weeks. DMBA uptake by inhalation was 76%. The amine was quickly distributed and biotransformed to nearly 100%. DMBA was eliminated in the urine with a half-time of 4.3 h. More than 50% was eliminated within 2 h of exposure. However, at all exposure levels the subjects continued to excrete DMBA the next morning. There was a significant correlation between the exposure to DMBA and the U-SumDMBA. Thus, U-SumDMBA may become an important biomarker for monitoring of industrial exposure to DMBA.

Early Pulmonary Cytokine Responses to Zinc Oxide Fume Inhalation

Zinc oxide inhalation causes metal fume fever, a flu-like syndrome common among welders. Proinflammatory pulmonary cytokines play a role in mediating this occupational illness. The goal of this investigation was to characterize early pulmonary cytokine responses after experimental human exposure to inhaled purified zinc oxide fume. We quantified bronchoalveolar lavage (BAL) cytokine concentrations in 15 healthy volunteers 3 hr after inhalation of zinc oxide fume. We compared postexposure cytokine responses with postsham exposure responses in the same 15 subjects. We also compared cytokine responses with those of 14 “late follow-up” subjects previously studied by BAL 20 hr after zinc oxide fume exposure. Zinc oxide exposure was a statistically significant, dose-dependent predictor of increases in BAL TNF (mean exposure–sham difference ± SE = 9.5 ± 3.6 pg/mL,P= 0.02), IL-6 (mean exposure–sham difference ± SE = 5.5 ± 1.8 pg/mL,P= 0.009), and IL-8 (mean exposure–sham difference ± SE = 64.1 ± 23.9 pg/mL,P= 0.02). The TNF response was significantly greater at 3 hr follow-up compared with 20 hr follow-up, after adjusting for smoking status, zinc dose, and BAL macrophages (P= 0.004). Our findings provide evidence for a pulmonary inflammatory response 3 hr after inhalation of zinc oxide fume characterized by dose-dependent increases in BAL proinflammatory cytokine concentrations. These data indicate that TNF plays an important initial role in mediating metal fume fever.

Biological monitoring of experimental human exposure to trimethylbenzene

Trimethylbenzene (TMB) is a component of numerous commercial preparations of organic solvents (Farbasol, Solvesso, Shellsol) used in the chemical, plastics, printing and other industries. TMB is a mixture of three isomers (pseudocumene-1,2,4-TMB; mesitylene-1,3,5-TMB; hemimellitene-1,2,3-TMB). The proportion of individual isomers in the mixture differs. The aim of this study was to obtain toxicokinetic data on the absorption and elimination of trimethylbenzene and its metabolites in biological fluids and to investigate the relationship between the biological indices of exposure and the absorbed dose. Eight-hour inhalation tests were performed in a toxicological chamber. The subjects were eight volunteers aged 20–39 with no history of exposure to TMB. They were exposed to pseudocumene, mesitylene or hemimellitene at concentrations ranging from 5 to 150 mg/m 3 air. Exhaled air, capillary blood and urine samples were collected before, during and after the exposure. The determinations of TMB or its metabolites were performed using gas chromatography (HP 5890 II Plus, MSD, FID). Pulmonary ventilation in the volunteers ranged from 0.56 to 1.0 m 3/h. The retention of 1,2,4-TMB; 1,3,5-TMB; 1,2,3-TMB in the lungs was 68%, 67% and 71%, respectively. The elimination of TMB from capillary blood occurred in accordance with the open three-compartment model. Urinary excretion of dimethylbenzoic acids (DMBA) proceeded according to the open two-compartment model. Based on the toxicokinetic data, a simulation model of accretion and excretion of DMBA in urine during a 14-day period was developed. The highest rates of metabolite excretion and the highest quantities of DMBA in urine during 24-h intervals were observed on day 5 of exposure. The relationship between the levels of TMB or DMBA in biological material and TMB air concentration or absorbed dose were determined. To select the urine fraction suitable for determining occupational TMB exposure, linear regression analysis was performed. The biological exposure limit (BEL) for TMB has been proposed, with the current maximum allowable concentration (MAC) value of 100 mg/m 3 (Polish standard) baseline value.