Individual Exposure Measurements Research Articles

Toxicogenomic profiling of chemically exposed humans in risk assessment.

Gene-environment interactions contribute to complex disease development. The environmental contribution, in particular low-level and prevalent environmental exposures, may constitute much of the risk and contribute substantially to disease. Systematic risk evaluation of the majority of human chemical exposures, has not been conducted and is a goal of regulatory agencies in the U.S. and worldwide. With the recent recognition that toxicological approaches more predictive of effects in humans are required for risk assessment, in vitro human cell line data as well as animal data are being used to identify toxicity mechanisms that can be translated into biomarkers relevant to human exposure studies. In this review, we discuss how data from toxicogenomic studies of exposed human populations can inform risk assessment, by generating biomarkers of exposure, early effect, and/or susceptibility, elucidating mechanisms of action underlying exposure-related disease, and detecting response at low doses. Good experimental design incorporating precise, individual exposure measurements, phenotypic anchors (pre-disease or traditional toxicological markers), and a range of relevant exposure levels, is necessary. Further, toxicogenomic studies need to be designed with sufficient power to detect true effects of the exposure. As more studies are performed and incorporated into databases such as the Comparative Toxicogenomics Database (CTD) and Chemical Effects in Biological Systems (CEBS), data can be mined for classification of newly tested chemicals (hazard identification), and, for investigating the dose-response, and inter-relationship among genes, environment and disease in a systems biology approach (risk characterization).

Arsenic in public water supplies and cardiovascular mortality in Spain

High-chronic arsenic exposure in drinking water is associated with increased cardiovascular disease risk. At low-chronic levels, as those present in Spain, evidence is scarce. In this ecological study, we evaluated the association of municipal drinking water arsenic concentrations during the period 1998-2002 with cardiovascular mortality in the population of Spain. Arsenic concentrations in drinking water were available for 1721 municipalities, covering 24.8 million people. Standardized mortality ratios (SMRs) for cardiovascular (361,750 deaths), coronary (113,000 deaths), and cerebrovascular (103,590 deaths) disease were analyzed for the period 1999-2003. Two-level hierarchical Poisson models were used to evaluate the association of municipal drinking water arsenic concentrations with mortality adjusting for social determinants, cardiovascular risk factors, diet, and water characteristics at municipal or provincial level in 651 municipalities (200,376 cardiovascular deaths) with complete covariate information. Mean municipal drinking water arsenic concentrations ranged from <1 to 118 microg/L. Compared to the overall Spanish population, sex- and age-adjusted mortality rates for cardiovascular (SMR 1.10), coronary (SMR 1.18), and cerebrovascular (SMR 1.04) disease were increased in municipalities with arsenic concentrations in drinking water > 10 microg/L. Compared to municipalities with arsenic concentrations < 1 microg/L, fully adjusted cardiovascular mortality rates were increased by 2.2% (-0.9% to 5.5%) and 2.6% (-2.0% to 7.5%) in municipalities with arsenic concentrations between 1-10 and >10 microg/L, respectively (P-value for trend 0.032). The corresponding figures were 5.2% (0.8% to 9.8%) and 1.5% (-4.5% to 7.9%) for coronary heart disease mortality, and 0.3% (-4.1% to 4.9%) and 1.7% (-4.9% to 8.8%) for cerebrovascular disease mortality. In this ecological study, elevated low-to-moderate arsenic concentrations in drinking water were associated with increased cardiovascular mortality at the municipal level. Prospective cohort studies with individual measures of arsenic exposure, standardized cardiovascular outcomes, and adequate adjustment for confounders are needed to confirm these ecological findings. Our study, however, reinforces the need to implement arsenic remediation treatments in water supply systems above the World Health Organization safety standard of 10 microg/L.

Maternal smoking during pregnancy and testicular cancer in the sons: A nested case–control study and a meta-analysis

Some large ecological studies have noted a significant association of testicular cancer (TC) with maternal smoking during pregnancy, while several more controlled studies have been negative. It has been difficult to obtain reliable data on exposure because of the long lag time to cancer diagnosis. We performed a case–control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal smoking in the risk of TC in the offspring. After reviewing the literature, we also performed a meta-analysis of published studies. For each index mother of the TC patient, three to nine matched control mothers with a cancer-free son born at the same time as the TC case were identified within each cohort. First trimester sera were retrieved from the 70 index mothers and 519 control mothers and were tested for cotinine level by a novel HPLC–MS–MS method developed. No statistically significant association between maternal cotinine level and risk of TC in the offspring was found (OR 0.68; 95% CI 0.35, 1.34). This is the first study based on individual exposure measurements. Its results agree with our meta-analysis of seven previous epidemiological studies (total number of 2149 cases, 2762 controls) using indirect exposure assessment (OR 1.0; 95% CI 0.88, 1.12).

Application of a dynamic population-based model for evaluation of exposure reduction strategies in the baking industry

Recently a dynamic population model was developed that simulates a population of bakery workers longitudinally through time and tracks the development of work-related sensitisation and respiratory symptoms in each worker. Input for this model comes from cross-sectional and longitudinal epidemiological studies which allowed estimation of exposure response relationships and disease transition probabilities This model allows us to study the development of diseases and transitions between disease states over time in relation to determinants of disease including flour dust and/or allergen exposure. Furthermore it enables more realistic modelling of the health impact of different intervention strategies at the workplace (e.g. changes in exposure may take several years to impact on ill-health and often occur as a gradual trend). A large dataset of individual full-shift exposure measurements and real-time exposure measurements were used to obtain detailed insight into the effectiveness of control measures and other determinants of exposure. Given this information a population wide reduction of the median exposure with 50% was evaluated in this paper.

Residential Outdoor Air Pollution and Lung Function in Schoolchildren

Long-term exposure to outdoor air pollution has typically been estimated on the aggregate level, and more individual measures of exposure are needed. We investigated the associations with lung function of residential outdoor air pollution in early life, total lifetime, and days before lung function test. In 2001-2002, spirometry was performed in 2307 9- and 10-year-old children who had lived in Oslo, Norway, since birth. Outdoor air pollution exposure for each child was assessed by the EPISODE dispersion model, calculating hourly concentrations of nitrogen dioxide (NO2), particulate matter (PM) with aerodynamic diameter less than 10 microm (PM10) and 2.5 microm (PM2.5). We applied linear regression analysis stratified by sex. Early and lifetime exposures to outdoor air pollution were associated with reduced peak expiratory flow and reduced forced expiratory flow at 25% and 50% of forced vital capacity, especially in girls. One interquartile increase of lifetime exposure to NO2, PM10, and PM2.5 was associated with change in adjusted peak respiratory flow of, respectively, -79 mL/s (95% confidence interval = -128 to -31), -66 mL/s (-110 to -23), and -58 mL/s (-94 to -21). We also found short-term effects of NO2 that became stronger with increasing time lags, but no short-term effects of PM. When we included short- and long-term NO2 exposures simultaneously, only the long-term effect remained. We found no effect on forced volumes. Adjusting for a contextual socioeconomic factor diminished the associations. Short- and long-term residential exposures to traffic-related pollutants in Oslo were associated with reduced peak expiratory flow and forced expiratory flow at 25% and 50% in 9- to 10-year-old children, especially in girls, with weaker associations after adjusting for a contextual socioeconomic factor.

Spatial Distribution of Orofacial Cleft Defect Births in Harris County, Texas, 1990 to 1994, and Historical Evidence for the Presence of Low-level Radioactivity in Tap Water

While both ionizing and nonionizing radiation are known to impair human reproductive capacity, the role of low-level domestic radiation continues to be an unsettled issue. We examined the geostatistical distribution (residential longitude and latitude) of orofacial cleft birth cases adjusted for the underlying population distribution. Furthermore, we examined the cleft birth rates enumerated by zip codes for possible associations with levels of radium and radon in drinking water. Cleft births and unaffected live births in Harris County, Texas, from 1990 to 1994, were geocoded by residential addresses and tested for spatial clusters using the space-time clustering program SaTScan. Historical sample data on local variations in water quality facilitated the assessment of the association of orofacial cleft defect births with low-level radiation exposure. A cluster of significantly greater than expected numbers of cleft defect births was identified in northwest Harris County, (relative risk = 3.0, P = 0.043), where the presence of elevated levels of radium (> 3 pCi/L) and radon (> 300 pCi/L) in the tap water has been known since the 1980s. Despite the ecological design of the study, lacking individual exposure measurements for cleft birth residences, there was strong suggestive evidence of an association between elevated radiation levels in tap water and elevated cleft birth prevalence rates by zip codes. Attention of physicians is invited to environmental causes as potential risk factors for orofacial cleft. This would aid in genetic counseling and the development of future preventive measures.

Relationship between indoor, outdoor, and personal fine particle concentrations for individuals with COPD and predictors of indoor-outdoor ratio in Mexico city

Personal exposure and indoor and outdoor exposure to PM(10) and PM(2.5) of 38 individuals with chronic obstructive pulmonary disease (COPD) was characterized from February through November 2000. All participants lived in Mexico City and were selected based on their area of residence southeast (n=15), downtown (n=15), and southwest (n=8). Participants were monitored at home using personal PM(2.5) monitoring devices. Indoor and outdoor levels of PM(10) and PM(2.5) were measured using MiniVol samplers. Concurrent individual exposure measurements, indoor and outdoor levels of PM(2.5), which averaged 38.4 (SD 21.4), 30.6 (SD 15.8), and 30.5 mug/m(3) (SD 19.4), respectively. Indoor PM(2.5) concentrations explained 40% of the variability of personal exposure. In addition, the factors that most affected personal exposure were regular indoor contact with animals, mold, cooking activities, and aerosol use, indicating that internal sources may largely affect individual exposure.

UV-France. Measurement of Individual and Population Exposure to Ultraviolet Radiation Based on Data from Meteorological Satellites

The project aims to quantify the spectrum of ultraviolet exposure in the various regions of France and its effects on the incidence of skin cancers and of other cancers possibly influenced by sun exposure (e.g. non-hodgkin lymphomas) and on the incidence of eye conditions likely influenced by exposure to solar ultraviolet radiation (cataract, age-linked macular degenerescence). By monitoring regional changes it would be possible to predict changes in health impact. UV-FRANCE will provide the first quantification of individual UV exposure of different age and gender population categories, and identify time trends. UV-FRANCE will provide indicators of exposure to the various fractions of the UV radiation, and use past UV exposure experience to predict global burden in future years (non-melanoma skin cancers, melanoma, cataract). By developing a sustainable monitoring of changes in UV exposure dose, likely changes in disease occurrence should be able to be predicted.

Reply to comments on “Derivation of numerical values for the World Health Organization guidelines for recreational waters”

The contribution addressed reveals an optimistic design philosophy likely to systematically underestimate risk in epidemiologic studies into the health effects of bathing water exposures. The authors seem to recommend that data on the ‘exposure’ measure (i.e. water quality) in such studies should be acquired in a similar manner to that used for regulatory sampling. This approach may compromise the quality of the epidemiologic investigations undertaken. It may result in imprecise estimates of exposure because it ignores the fact that regulatory timescales and spatial resolution (even if artificially compressed to a bathing day) can mask large spatial and temporal variability in water quality. If this variability is ignored by taking some mean value and attributing that to all of those exposed in a period at a study location, many bathers may be misclassified and the studies may be biased to a ‘no-effect’ conclusion. A more appropriate approach is to maximise the precision of the epidemiologic investigations by measurement of individual exposure (or water quality) at the place and time of the exposure, as has been done in randomised volunteer studies in the UK and Germany. The precise epidemiologic relationships linking ‘exposure’ with ‘illness’ can then be related to the probability of exposure to particular water quality by a ‘normal bather’ using the known probability distribution of the exposure variable (i.e. faecal indicator concentration) in the regulated bathing waters. We suggest that any research protocol where poor sampling design for water quality assessment is justified because regulatory monitoring is equally imprecise may be fundamentally flawed. The rationale for this assessment is that the epidemiology is the starting point and evidence-base for ‘standards’. If precision is not maximised at this stage in the process it compromises the credibility of the standards design process. The negative effects of the approach advocated in this ‘comment’ are illustrated using published research findings used to derive the figures illustrated in Wymer et al. [2005. Comment on derivation of numerical values for the World Health Organization guidelines for recreational waters. Water Research 39, 2774–2777].

Direct, indirect influences of income on road traffic noise annoyance

Studies of human reactions to noise have often also studied possible impacts of nonacoustic variables such as income, education and occupational status. While such social status variables have been shown to modify health outcomes they do not have any important effect in noise-annoyance studies. However, the socio-acoustic research analyses usually employ regression models where the noise each person is exposed to is regarded as exogenous, i.e given. This precludes the analysis of indirect effects, such as wealthy people buying themselves out of noisy neighbourhoods. To explore this type of indirect effects, the relationship between noise exposure, income and noise annoyance is investigated a step further in this paper. Structural equation models incorporating both direct and indirect pathways have been estimated using data from six socio-acoustic surveys combining individual noise exposure measures with questions on noise perception and background characteristics. The hypothesis that high-income groups buy themselves free from noise is only partly confirmed. It seems to hold true for residents of a small-to-medium size city, but not for residents of a larger city. With respect to income as a possible modifier of annoyance, the previous results that no such moderating effects can be found are confirmed.

Application of air quality models to public health analysis

Although measurements of individual exposure remain the “gold standard” for evaluating health risks associated with air pollution, atmospheric models have become important tools for understanding the links between energy use, air pollution, and public health. The spatial and temporal coverage of model data typically far exceeds that of measurement data; the cost of simulating air pollution concentrations with a model is low compared with the equipment and personnel costs to operate a network of measurement stations; and models permit analysis of future projections and implications of air quality management policy. Still, important limitations remain. No model is perfect, and data quality is limited by model accuracy, meteorological input, and quantification of emissions. Exploiting the strengths of models in public health analysis, while appropriately dealing with model uncertainty, poses challenges that span public health and atmospheric science disciplines. Here we review past studies in which models have been employed in air pollution health analyses, and we discuss new directions in public health that capitalize on atmospheric model strengths.

Arsenic: In Search of an Antidote to a Global Poison

Arsenic. No other element has such a complex and variegated past. As early as 500 B.C. the ancients knew about arsenic, whose name comes from the Greek word for potent. Through the centuries, this “king of poisons” was a common means of homicide. And yet, arsenic’s image has not always been so morbid. People in the Middle Ages wore arsenic amulets around their necks to ward off the bubonic plague, and women in Victorian times applied arsenic compounds to their faces to whiten their complexions. Hippocrates, the father of western medicine, recorded arsenic’s usefulness as a topical remedy for skin ulcers.

Micronuclei assessment in buccal cells of people environmentally exposed to arsenic in northern Chile

To determine the genotoxic risk associated to environmental arsenic exposure, the frequency of micronuclei in buccal cells (BCMN) of people drinking arsenic-contaminated water has been evaluated. A group of 105 individuals from the Antofagasta region (north Chile), and 102 individuals from the area of Concepción, used as reference group, were included in the study. Arsenic concentration in drinking water was high (0.75 mg/L) in the Antofagasta area, 75-fold the maximum recommended level by WHO (0.01 mg/L), while the values obtained in Concepción were significantly lower (0.002 mg/L). Individual measures of arsenic exposure were also determined in fingernails, which clearly confirm the existence of chronic exposure in the sampled populations from the Antofagasta region (10.15 μg/g versus 3.57 μg/g). The cytogenetic results indicate that, although the BCMN frequency is higher in exposed than in controls, this increase does not attain statistical significance. When the exposure biomarkers were related with the cytogenetic values, no correlations were observed between BCMN and arsenic content in water or in fingernails. In addition, the genotoxicity values do not seem to be related to the ethnic origin from people belonging to the exposed group. As a conclusion it appears that, in the studied population, the chronic ingestion of arsenic-contaminated water does not induce cytogenetic damage, measured as micronuclei, in the cells of the oral mucous in a significant extent.

Ocular lens blue autofluorescence cannot be used as a measure of individual cumulative UVR exposure.

The accumulation of fluorophores in the ocular lens with age might be caused by ultraviolet solar radiation (UVR) exposure, but evidence of a relation between individual cumulative UVR exposure and lens autofluorescence is lacking. Individually determined UVR exposure has never before been related to lens autofluorescence, and the aim of this study was to investigate if ocular lens blue autofluorescence can be used as a biological UVR dosimeter. Ocular lens autofluorescence was quantified in vivo by fluorescence spectroscopy in 145 volunteers (108 healthy subjects, 18 with basal cell carcinoma (BCC) and 19 with cutaneous malignant melanoma (MM)). The excitation wavelength was 350 nm and the fluorescence emission was 450 nm. Individual UVR exposure data were collected both retrospectively and prospectively using questionnaires and electronic personal UVR dosimeters. Lens blue autofluorescence increased significantly with age (P=0.01), and females had significantly higher autofluorescence than males (P=0.024); the two factors explained 10% of the total variation in lens autofluorescence. Neither smoking habits nor use of glasses/contact lenses or sunglasses influenced autofluorescence. No correlations between autofluorescence and UVR exposure measurements were found, and neither was there a difference in autofluorescence between groups with high and low UVR exposure (P-values>0.1), respectively. MM patients had significantly (P=0.019) higher autofluorescence than healthy subjects when age and sex differences were taken into account; no such difference (P=0.097) was detected between BCC patients and healthy subjects. The results indicate that age and gender only play a minor role in the level of lens blue autofluorescence. Exposure to UVR has been suggested to be responsible for a part of the age-related increase in autofluorescence, but this could not be confirmed in this study. The higher level of lens autofluorescence found in MM patients might be due to genetics rather than higher cumulative UVR exposure. In conclusion, ocular lens blue autofluorescence cannot be used as a biological UVR dosimeter.

Urban air pollution and mortality in a cohort of Norwegian men.

We investigated the association between total and cause-specific mortality and individual measures of long-term air pollution exposure in a cohort of Norwegian men followed from 1972-1973 through 1998. Data from a follow-up study on cardiovascular risk factors among 16,209 men 40-49 years of age living in Oslo, Norway, in 1972-1973 were linked with data from the Norwegian Death Register and with estimates of average yearly air pollution levels at the participants' home addresses from 1974 to 1998. Cox proportional-hazards regression was used to estimate associations between exposure and total and cause-specific mortality. During the follow-up time 4,227 men died from a disease corresponding to an ICD-9 (International Classification of Diseases, Revision 9) code < 800. Controlling for a number of potential confounders, the adjusted risk ratio for dying was 1.08 [95% confidence interval (CI), 1.06-1.11] for a 10- microg/m3 increase in average exposure to nitrogen oxides (NOx) at the home address from 1974 through 1978. Corresponding adjusted risk ratios for dying from a respiratory disease other than lung cancer were 1.16 (95% CI, 1.06-1.26); from lung cancer, 1.11 (95% CI, 1.03-1.19); from ischemic heart diseases, 1.08 (95% CI, 1.03-1.12); and from cerebrovascular diseases, 1.04 (95% CI, 0.94-1.15). The findings indicate that urban air pollution may increase the risk of dying. The effect seemed to be strongest for deaths from respiratory diseases other than lung cancer.

Respiratory symptoms and lung-function changes with exposure to five substances in aluminium smelters.

To determine whether exposure to five different occupational substances contributes to respiratory symptoms in aluminium smelter workers. A cross-sectional survey of 1,615 male employees of two Australian aluminium smelters was conducted in 1995. Subjects underwent spirometry and were asked about respiratory symptoms and the relationship of those symptoms to work. Their job histories were combined with a task exposure matrix to produce individual quantitative measures of cumulative exposure to fluoride, sulphur dioxide, inspirable dust, the benzene-soluble fraction of coal tar pitch volatiles (BSF), and oil mist. After adjusting for smoking and age, we found that subjects with the highest cumulative exposure to fluoride (>0.16 mg/m(3) years) and inspirable dust (>2.9 mg/m(3) years) were two to four times more likely to report work-related wheeze and chest tightness than were unexposed subjects. Lower prevalence ratios for the same symptoms were seen with sulphur dioxide and BSF. Levels of lung function decreased slightly with exposure to oil mist, but not with cumulative exposure to other substances. This study suggests that the relevant causative agents for respiratory symptoms in aluminium smelters are fluoride and inspirable dust.

The nasal air sampler: a device for sampling inhaled aeroallergens

The object is to design, develop, and test a personal aerosol sampling device consisting of impaction samplers worn just inside the nostrils, driven by the wearer's respiration. The device provides a novel and unique measure of individual exposure to aeroallergens. It was conceived as an integral part of an allergen diagnostic system, in which collected aerosols are immunostained with monoclonal antibodies or the patient's IgE and associated particles positively identified using techniques of image analysis. Each sampler comprises a slot impactor with a detachable impaction plate covered with either a specially developed medical adhesive or a protein-binding membrane. Sampler performance has been validated by rig tests of aerodynamic resistance and collection efficiency of different sized particles at various flow rates. There have also been field trials with human subjects which show that the sampler can be comfortably worn for periods of up to 4 hours. This is sufficient to gather a representative sample of inhaled allergens in most environments. The sampler collects an increasing proportion of particles in the inhalable range at and above 5 microm. This includes most bioaerosols of interest to allergists. Sampler prototypes have been built by CNC mill and stereolithography. Batches of samplers have been molded in biocompatible materials for field and clinical trials. The device successfully collects aeroallergens from a patient's own respiration. While developed specifically as a vehicle for the allergen diagnostic system, it can be adapted for studies of other aspects of air quality or for prophylactic use.

The Effect of Air Pollution on Infant Mortality Appears Specific for Respiratory Causes in the Postneonatal Period

To examine the association between individual lifetime measures of mean exposure to air pollution and postneonatal respiratory deaths, we have conducted a matched population-based case-control study covering all births registered in the Czech Republic from 1989 to 1991 that were linked to death records. For each case of infant death, we have randomly selected 20 controls from infants of the same sex born on the same day and alive when the case died. Exposure was assigned as the arithmetic mean of all 24-hour air pollution measurements in the district of residence of each case and control for the period between the birth and death of the index case. We used conditional logistic regression to estimate the effects of suspended particles, sulfur dioxide, and nitrogen oxides on risk of death in the neonatal and postneonatal period, controlling for maternal socioeconomic status and birth weight, birth length, and gestational age. There were 2,494 infant deaths with exposure data on at least one pollutant, 133 of them from respiratory causes. The effects of all pollutants were strongest in the postneonatal period and were specific for respiratory causes. For these, rate ratios for a 50 microg/m3 increase in particles, sulfur dioxide, and nitrogen oxides were 1.95 [95% confidence interval (CI) = 1.09-3.50], 1.74 (95% CI = 1.01-2.98), and 1.66 (95% CI = 0.98-2.81), respectively, after controlling for all covariates. Only particles showed a consistent association when all pollutants were entered in one model. We found no evidence of a relation between any pollutant and mortality from other causes. These results indicate that the effects of air pollution on infant mortality are specific for respiratory causes in the postneonatal period, are independent of socioeconomic factors, and are not mediated by birth weight or gestational age.

Occupational exposure to environmental tobacco smoke: results of two personal exposure studies.

Personal monitoring is a more accurate measure of individual exposure to airborne constituents because it incorporates human activity patterns and collects actual breathing zone samples to which subjects are exposed. Two recent studies conducted by our laboratory offer perspective on occupational exposure to environmental tobacco smoke (ETS) from a personal exposure standpoint. In a study of nearly 1600 workers, levels of ETS were lower than or comparable to those in earlier studies. Limits on smoking in designated areas also acted to reduce overall exposure of workers. In facilities where smoking is permitted, ETS exposures are 10 to 20 times greater than in facilities in which smoking is banned. Service workers were exposed to higher levels of ETS than workers in white-collar occupations. For the narrower occupational category of waiters, waitresses, and bartenders, a second study in one urban location indicated that ETS levels to which wait staff are exposed are not considerably different from those exposure levels of subjects in the larger study who work in environments in which smoking is unrestricted. Bartenders were exposed to higher ETS levels, but there is a distinction between bartenders working in smaller facilities and those working in multiroom restaurant bars, with the former exposed to higher levels of ETS than the latter. In addition, ETS levels encountered by these more highly exposed workers are lower that those estimated by the Occupational Safety and Health Administration. Concomitant area monitoring in the smaller study suggests that area samples can only be used to estimate individual personal exposure to within an order of magnitude or greater.

Measurement of individual human exposure to atmospheric pollutants (in French)

Measurement of individual human exposure to atmospheric pollutants (in French)