Toxicological Exposure Research Articles

Determining the volume of toxic liquid ingestions in adults: accuracy of estimates by healthcare professionals and members of the public

Context. Ingestion of toxic liquids is common, and the volume ingested is often important for clinical decision-making. However, the accuracy and interpretation of volume estimates in the context of toxicological exposures is poorly characterised in adult practice. Objective. To inform the interpretation of volume estimates when expressed in forms commonly encountered in toxicological practice: (1) semi-quantitative volume descriptors, such as ‘mouthfuls’; (2) quantitative self-estimates of ingestion volume, for example, millilitres; and (3) estimates of residual volume in containers. Methods. In the first part of the study, 50 members of the public ingested water in response to requests to take a ‘small mouthful’, ‘large gulp’ and ‘five mouthfuls’. They estimated the amount ingested, and actual volumes were measured. In part 2, 15 members of the public and 15 healthcare professionals estimated the volumes contained in 12 opaque and transparent bottles. Results. The mean age of participants in part 1 was 37 years, and in part 2 it was 34 years. The mean volume (95% prediction interval) of a ‘small mouthful’ was 43 (3–137) mL; ‘large gulp’, 77 (20–168) mL; and ‘five mouthfuls’, 157 (25–375) mL. The mean error (95% limits of agreement) for self-estimates of ingestion volume was an underestimate of − 52% (− 90% to + 124%). Volume contained in bottles was underestimated by − 5% (− 38% to + 27%). This varied according to the container type (mean difference: opaque, − 10%; transparent, − 1%; P < 0.01) and participant type (members of the public, − 8%; healthcare professionals, − 3%; P = 0.02). Conclusions. Volume estimates derived from semi-quantitative descriptors are not a reliable basis for clinical decision-making. Self-estimates provided in a quantitative form are inaccurate and prone to underestimation. Estimates of residual volume in containers should be regarded as suspect if the container is opaque. Where clinical decisions hinge on the volume ingested, efforts should be made to quantify this using measurement.

Fluoride in Groundwater: Toxicological Exposure and Remedies

Fluoride is a chemical element that is found most frequently in groundwater and has become one of the most important toxicological environmental hazards globally. The occurrence of fluoride in groundwater is due to weathering and leaching of fluoride-bearing minerals from rocks and sediments. Fluoride when ingested in small quantities (<0.5 mg/L) is beneficial in promoting dental health by reducing dental caries, whereas higher concentrations (>1.5 mg/L) may cause fluorosis. It is estimated that about 200 million people, from among 25 nations the world over, may suffer from fluorosis and the causes have been ascribed to fluoride contamination in groundwater including India. High fluoride occurrence in groundwaters is expected from sodium bicarbonate-type water, which is calcium deficient. The alkalinity of water also helps in mobilizing fluoride from fluorite (CaF2). Fluoride exposure in humans is related to (1) fluoride concentration in drinking water, (2) duration of consumption, and (3) climate of the area. In hotter climates where water consumption is greater, exposure doses of fluoride need to be modified based on mean fluoride intake. Various cost-effective and simple procedures for water defluoridation techniques are already known, but the benefits of such techniques have not reached the rural affected population due to limitations. Therefore, there is a need to develop workable strategies to provide fluoride-safe drinking water to rural communities. The study investigated the geochemistry and occurrence of fluoride and its contamination in groundwater, human exposure, various adverse health effects, and possible remedial measures from fluoride toxicity effects.

Bio-concentration of fluoride in Lady's finger (Abelmoschus esculentus) grown in contaminated alkaline soil and evaluation of exposure risk in human

A pot culture study was conducted to evaluate the bio-accumulation of fluoride (F) in terms of bio-concentration factor (BCF) in Lady's finger (Abelmoschus esculentus) when grown in sodium F (NaF) contaminated alkaline soil. Toxicological exposure risk on humans in terms of estimated daily intake was assessed. It was found that the maximal F accumulation took place in roots (16.64–106.2 mg kg−1), whereas in the edible part (fruit), it varied between 39.3 to 48.51 mg kg−1 in the treatment range of 0–600 mg NaF kg−1 soil. The order of F accumulation in plant tissues followed root > leaf > fruit > shoot. The BCF values in the fruit showed a decreasing trend (6.74–5.17 mg .plant mg−1 soil), whereas in root, it increased (6.69–12.27 mg of plant per mg soil) with the rise in added F (100 mg F per kg soil to 600 mg F per kg soil). The risk of F exposure due to the consumption of fruit was estimated for an adult (18–70 years), which were found to be 0.001 mg kg−1 day−1 at the minimum F concentration of 39.3 mg kg−1 (dwt.) and 0.0013 mg kg−1 day−1 at the maximum F concentration of 48.51 mg kg−1 (dwt.) of fruit.

Modelling potential β-carotene intake and cyanide exposure from consumption of biofortified cassava.

Vitamin A (VA) deficiency causes disability and mortality. Cassava can be crossbred to improve its β-carotene (BC) content; typical white cassava contains negligible amounts of BC. However, cassava contains cyanide and its continued consumption may lead to chronic disability. Our objective was to estimate the risk-benefit of consuming BC-enhanced cassava to increase VA intake. A total of ten American women were fed white and BC-enhanced cassava. BC and cyanide data from the feeding study were combined with African cassava consumption data to model the potential daily BC, VA and cyanide intakes of African women. If BC-enhanced cassava replaced white cassava in the diets, it could theoretically meet recommended VA intakes for the following percentages of individuals from six African countries that consume cassava as a staple crop: Angola (95%), Central African Republic (95%), Congo (about 100%), Ghana (99%), Mozambique (99%) and Nigeria (92%). Cyanide intake after minimal preparation of cassava could be thirteen to thirty-two times the reference dose (RfD), a toxicological exposure reference, but could be completely removed by extensive soaking. This study demonstrates that consumption of BC-enhanced cassava, processed to maintain BC and remove cyanide, theoretically increases VA intakes for African populations and other areas of the world where cassava is a staple crop.

Pesticide Exposure in Children

This statement presents the position of the American Academy of Pediatrics on pesticides. Pesticides are a collective term for chemicals intended to kill unwanted insects, plants, molds, and rodents. Children encounter pesticides daily and have unique susceptibilities to their potential toxicity. Acute poisoning risks are clear, and understanding of chronic health implications from both acute and chronic exposure are emerging. Epidemiologic evidence demonstrates associations between early life exposure to pesticides and pediatric cancers, decreased cognitive function, and behavioral problems. Related animal toxicology studies provide supportive biological plausibility for these findings. Recognizing and reducing problematic exposures will require attention to current inadequacies in medical training, public health tracking, and regulatory action on pesticides. Ongoing research describing toxicologic vulnerabilities and exposure factors across the life span are needed to inform regulatory needs and appropriate interventions. Policies that promote integrated pest management, comprehensive pesticide labeling, and marketing practices that incorporate child health considerations will enhance safe use.

Toxicologic Exposures Associated With Natural Disasters: Gases, Kerosene, Ash, and Bites

Natural disasters such as earthquakes, hurricanes, tornadoes, floods, and volcanic eruptions may increase human exposures to toxins. Disaster management encompasses a continuous cycle involving preparedness, response, recovery, and mitigation. Toxic exposures occur in predictable segments of the disaster cycle. Although carbon monoxide poisoning is the most widely reported poisoning after natural disasters, other toxins including certain hydrocarbons, volcanic ash, and gases, as well as snake and animal bites, are also recognized hazards. Emergency response personnel and health care providers should be aware of these hazards to respond and manage these exposures effectively. This article will present an overview of toxic exposures related to natural disasters, specifically, carbon monoxide, hydrocarbons/petroleum distillates, volcanic ash, animal exposures, and snake bites. Their relation to the disaster management cycle will be presented to serve as a primer for medical personnel and health care providers assisting with disaster response or emergency planning.

Are Differences in MicroRNA Regulation Implicated in Species-Dependent Response to Toxicological Exposures?

Equivalent exposures can result in qualitatively or quantitatively dissimilar toxic effects across species, with the underlying molecular mechanisms being often not well defined. In many cases, differences in metabolic handling of the chemical (metabolism and disposition) provide an explanation of these differences, but in other cases the explanation is less obvious. This variability in the outcome of toxicant exposures complicates the interspecies extrapolation of human hazard from animal testing data. MicroRNAs (miRNAs) are a family of noncoding RNAs that posttranscriptionally regulate the expression of their target genes that have fundamental roles in physiology, disease, and toxicological responses. Importantly, these noncoding genes are characterized by a high evolutionary flux, in terms of miRNA repertoire and functioning, even among closely related species. Furthermore, evidence is emerging that the enzymes of drug metabolism are also under miRNA regulation and thus offer a new twist to an old para digm, whereby manipulation of the expression of these enzymes affects toxic outcomes. In this review, we discuss how miRNA may contribute to the interspecies variability observed in the response to toxicant exposures. Although few studies have so far specifically examined the contribution of differences in miRNA regulation to species-dependent responses to toxicological exposures, we believe that this will be an area of intense research in the coming years.

High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring

High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: (1) whether more chemicals are detected in humans living in a less controlled environment than captive species and (2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537–3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.

Banding the World Together; The Global Growth of Control Banding and Qualitative Occupational Risk Management

Control Banding (CB) strategies to prevent work-related illness and injury for 2.5 billion workers without access to health and safety professionals has grown exponentially this last decade. CB originates from the pharmaceutical industry to control active pharmaceutical ingredients without a complete toxicological basis and therefore no occupational exposure limits. CB applications have broadened into chemicals in general - including new emerging risks like nanomaterials and recently into ergonomics and injury prevention. CB is an action-oriented qualitative risk assessment strategy offering solutions and control measures to users through "toolkits". Chemical CB toolkits are user-friendly approaches used to achieve workplace controls in the absence of firm toxicological and quantitative exposure information. The model (technical) validation of these toolkits is well described, however firm operational analyses (implementation aspects) are lacking. Consequentially, it is often not known if toolkit use leads to successful interventions at individual workplaces. This might lead to virtual safe workplaces without knowing if workers are truly protected. Upcoming international strategies from the World Health Organization Collaborating Centers request assistance in developing and evaluating action-oriented procedures for workplace risk assessment and control. It is expected that to fulfill this strategy's goals, CB approaches will continue its important growth in protecting workers.

Latent class models for joint analysis of disease prevalence and high-dimensional semicontinuous biomarker data

High-dimensional biomarker data are often collected in epidemiological studies when assessing the association between biomarkers and human disease is of interest. We develop a latent class modeling approach for joint analysis of high-dimensional semicontinuous biomarker data and a binary disease outcome. To model the relationship between complex biomarker expression patterns and disease risk, we use latent risk classes to link the 2 modeling components. We characterize complex biomarker-specific differences through biomarker-specific random effects, so that different biomarkers can have different baseline (low-risk) values as well as different between-class differences. The proposed approach also accommodates data features that are common in environmental toxicology and other biomarker exposure data, including a large number of biomarkers, numerous zero values, and complex mean-variance relationship in the biomarkers levels. A Monte Carlo EM (MCEM) algorithm is proposed for parameter estimation. Both the MCEM algorithm and model selection procedures are shown to work well in simulations and applications. In applying the proposed approach to an epidemiological study that examined the relationship between environmental polychlorinated biphenyl (PCB) exposure and the risk of endometriosis, we identified a highly significant overall effect of PCB concentrations on the risk of endometriosis.

Application of the biotic ligand model to predict copper acute toxicity to Medaka fish in typical Chinese rivers

LA50, the Lethal Accumulation of Cu on the Medaka fish (Oryzias latipes) gills that results in 50% mortality during a toxicological exposure (96 hours) in synthetic water was assessed by use of the biotic ligand model (BLM). The LA50 was employed to predict the 96 h Cu toxicity (LC50) to this fish in different natural surface waters in China. The LC50 values were predicted with errors of no more than 1.55 for the river water except for two water samples, one of which was from a tidal river and the other of which was from a river that was subject to joint metal pollution and possibly affected by other pollutants.

Behavioral Epigenetics: How Nurture Shapes Nature

Identical twins have the same genes. Yet as individuals, they can be quite unalike in behavior, in personality, in health, and even in appearance, and they tend to grow more different as they age. How can genes that seem to be identical produce such different effects? A big part of the answer, scientists now think, is epigenetics—how nurture shapes nature. Epigenetic mechanisms are molecular events that govern the way the environment regulates the genomes of organisms. Epigenetic processes lead to individual differences in appearance, physiology, cognition, and behavior—the group of traits known as the phenotype. Scientists are at the very earliest stages of investigating them. The goal is to pry open one of nature’s most challenging black boxes: explaining how life experiences are transmuted into persistent changes in body function and behavior. In its brief history, epigenetics research has concentrated mostly on the early development of organisms. One strain of these investigations is development of behavior, and this line of research now has its own name: Behavioral epigenetics refers to the study of how signals from the environment trigger molecular biological changes that modify what goes on in brain cells. Here, the term environment mechanisms of memory—changes driven by experience—in the adult nervous system. “It’s not just that development and behavioral memory are rough analogs of each other, but rather that they are molecular homologues of each other,” he says. The two most studied epigenetic processes— regulation of the structure of threedimensional DNA and its associated proteins, plus chemical adjustments to DNA through mechanisms like histone modification—are essential both in development and in long-term memory formation. “It’s as if evolution has been efficient in the set of molecular mechanisms that cells use to trigger persisting changes. It uses those mechanisms in development when it’s patterning the organism, when it’s turning an embryonic stem cell into a neuron or a liver cell,” he says. “Then in the adult nervous system it has coopted some of those same mechanisms to trigger experience-dependent, persisting change in the function of neurons in the nervous system.” Several studies have established that both DNA methylation and histone modifications are essential for learning and remembering. Some examples are based on fear conditioning, in which mice learn to show fear of a particular location where they have been subjected to electric shocks. encompasses pretty much everything that happens in every stage of life: social experience; nutrition; hormones; and toxicological exposures that occur prenatally, postnatally, and in adulthood. If research on epigenetics is in its infancy, research on behavioral epigenetics is in embryo. Despite its embryonic state, behavioral epigenetics is already a vast topic, rife with complexities that grow more intricate every day. Discoveries seem to lead not to illumination but to more questions, and we have space here to touch on barely a few. Yet behavioral epigenetics has been held out as promising to elucidate, and perhaps even solve, immense medical troubles, such as mental retardation, autism, schizophrenia, and neurodegenerative disorders, and even social challenges, such as aging, addiction, suicide, child abuse, and child neglect.

Laboratory evaluation of a prototype photochemical chamber designed to investigate the health effects of fresh and aged vehicular exhaust emissions

Laboratory experiments simulating atmospheric aging of motor vehicle exhaust emissions were conducted using a single vehicle and a photochemical chamber. A compact automobile was used as a source of emissions. The vehicle exhaust was diluted with ambient air to achieve carbon monoxide (CO) concentrations similar to those observed in an urban highway tunnel. With the car engine idling, it is expected that the CO concentration is a reasonable surrogate for volatile organic compounds (VOCs) emissions. Varying the amount of dilution of the exhaust gas to produce different CO concentrations, allowed adjustment of the concentrations of VOCs in the chamber to optimize production of secondary organic aerosol (SOA) needed for animal toxicological exposures. Photochemical reactions in the chamber resulted in nitric oxide (NO) depletion, nitrogen dioxide (NO2) formation, ozone (O3) accumulation, and SOA formation. A stable SOA concentration of approximately 40 μg m−3 at a chamber mean residence time of 30 min was achieved. This relatively short mean residence time provided adequate chamber flow output for both particle characterization and animal exposures. The chamber was operated as a continuous flow reactor for animal toxicological tests. SOA mass generated from the car exhaust diluted with ambient air was almost entirely in the ultrafine mode. Chamber performance was improved by using different types of seed aerosol to provide a surface for condensation of semivolatile reaction products, thus increasing the yield of SOA. Toxicological studies using Sprague-Dawley rats found significant increases of in vivo chemiluminescence in lungs following exposure to SOA.

Ca and Mg determination from inhabitants of Brazil using neutron activation analysis

In this study the neutron activation analysis (NAA) technique was applied to determine Ca and Mg in whole blood from inhabitants of Brazil for the purpose of establishing concentration ranges indicative of sex and age. The initiative to perform these measurements is related to the increase in heart disease. According to recent statistics from WHO, the average is one death due to heart attack in Brazil, every five minutes. The measures were performed considering lifestyle factors (non-smokers, non-drinkers and no history of toxicological exposure) of Brazilian inhabitants. A healthy group constituted of male (n = 94) and female (n = 84) blood donors, ages between 18 and 70 years and above 50 kg, was selected from the blood banks and hematological laboratories of Brazil. The influence of sex was also investigated considering several age ranges (18–29, 30–40, 41–50, >50 years). The results show significant differences when a comparison is made by sex and age and may be useful to identify or prevent clinical diseases. These results emphasize the need to perform periodic evaluation of Ca and Mg in blood.

Preface: metals in the brain

At the beginning of the last century a newborn in Europe had a life expectancy of about 45 years. Now, approximately 100 years later, this number has increased in the West to more than 80 years [1]. The reasons for this extended life span are manyfold, the more important ones being improved hygiene, progress in medicine, a reduced mortality of mother and child, control of epidemics, and better food provisions [2]. As we all know, this has led to a tremendous growth of the world population: About 1 billion (=10) people inhabited the Earth in 1804; it took nearly 125 years to double this number, by 1974 it was 4 billion, and the estimate for 2025 is 8 billion [1]. However, this story of success has a seamy side: because of the increased life span, cancer and other age-related diseases, especially those connected with neurodegeneration, mainly manifested in the brain, are getting more and more prominent. To this category belong, among others, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), transmissible spongiform encephalopathy (prion disease; Creutzfeldt–Jakob disease), neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden–Spatz disease), Friedreich’s ataxia, progressive supranuclear palsy (PSP), and multisystem atrophy (MSA) [3]. The best known of these debilitating illnesses are certainly Alzheimer’s [3] and Parkinson’s [3, 4] diseases. About 29 million people worldwide suffered from Alzheimer’s disease in 2009; this is about 60% of those being affected by dementia. Computer models predict that the number of patients with AD will increase to 106 million by 2050 [1], which means one per 85 persons—even if this number should be off by a factor of 2, one out of 170 persons is still truly frightening! It is an old wisdom that metals are indispensable for life; in fact, several of them, like sodium, potassium, and calcium, are easily discovered in living matter [5]. However, the role of metals and their impact on life remained largely hidden until inorganic chemistry and coordination chemistry experienced a pronounced revival in the middle of the last century. The experimental and theoretical tools created and their application to biochemical problems led to the development of the field or discipline Bioinorganic Chemistry, which was established by 1970. It also became known as Inorganic Biochemistry and more recently as Biological Inorganic Chemistry [3]. At present there is substantial evidence that metal ions play a significant role in the pathogenesis and pathophysiology of neurodegenerative diseases, which reveal themselves mainly in the brain. This is not surprising because the brain utilizes metal ions for a myriad of biochemical reactions. The metal-related disorders are caused (1) by defects in metal ion transport or homeostasis, (2) by toxicological exposure to metals, and (3) they are associated with metalloprotein aggregation and/or misfolding and oxidative reactions [3]. This organizational frame is certainly helpful, yet to assign a given illness to a distinct category is not easy because of our lack in understanding the mechanisms involved in a given disease, though misfolded proteins are often implicated. Of course, toxic metal ions like mercury or cadmium are easily categorized, but with essential metal ions like copper, iron, zinc, or manganese, which may be toxic as well, matters are considerably more difficult and we are only at the brink of understanding the fine line between essentiality and toxicity. There is an urgent need to unravel the A. Sigel H. Sigel (&) Department of Chemistry, Inorganic Chemistry, University of Basel, Spitalstrasse 51, 4056 Basel, Switzerland e-mail: Helmut.Sigel@unibas.ch

Titanium dioxide in our everyday life; is it safe?

BackgroundTitanium dioxide (TiO2) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO2 nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO2 nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO2 nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO2 nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO2 nanoparticles are classified as “possible carcinogenic to humans” by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO2 nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo-oxidation products. Although TiO2 is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO2 may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects.ConclusionsUntil relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO2 nanoparticles should be used with great care.

The Global Burden of Air Pollution on Mortality: Anenberg et al. Respond

Prueitt and Goodman raise concerns about our use of chronic ozone mortality relative risk (RR) estimates from Jerrett et al. (2009) to estimate the global burden of outdoor ozone and fine particulate matter (< 2.5 μm in aerodynamic diameter; PM2.5) on human mortality (Anenberg et al. 2010). We believe that our use of RR estimates from Jerrett et al. (2009) is justified and does not strongly affect our conclusions. Our goal of demonstrating the use of chemical transport models in estimating the global burden of outdoor air pollution on mortality is not affected by the choice of risk estimates. Further, using chronic RR estimates for ozone has only a minor effect on our mortality estimates, because the mortalities attributed to PM2.5 are much greater than those for ozone. We chose to use RR estimates from Jerrett et al. (2009) in our study (Anenberg et al. 2010) because they are consistent with the widely accepted RR estimates used for long-term PM2.5 mortality (Krewski et al. 2009), as both are based on the American Cancer Society study cohort and capture delayed mortality effects (National Research Council 2008). In response to particular criticisms, we note that while Jerrett et al. (2009) found the first significant positive association between chronic ozone exposure and mortality in a major cohort study, some previous smaller cohort studies have also found positive associations (National Research Council 2008). Biological plausibility for chronic ozone effects on respiratory mortality is evidenced by toxicology and human exposure studies that found that ozone affects airway inflammation, pulmonary function, and asthma induction and exacerbation (National Research Council 2008). Using earlier PM2.5 data would be unlikely to affect confounding in the model, because using PM2.5 data from 1979–1983 and 1999–2000 yields similar PM2.5 mortality associations (e.g., Krewski et al. 2009). Jerrett et al. (2009) also found that socioeconomic data are not strong confounders and that using more recent data is unlikely to change that conclusion (see Appendix of Jerrett et al. 2009). Finally, national risk estimates are more applicable globally than city-specific estimates because they include larger and more diverse populations. However, because the evidence for chronic ozone mortality is more limited than the large body of evidence demonstrating mortality associations with short-term ozone exposure, we present here estimates of the global burden of ozone on mortality using RR estimates from Bell et al. (2004), a large multicity study of short-term ozone mortality. We estimated mortalities daily using the difference between preindustrial and present-day 8-hr maximum ozone, and sum mortalities over the 1-year simulation. We used the reported relationship for cardiopulmonary mortality and daily average ozone [0.64% (95% posterior interval, 0.31–0.98%) for a 10-ppb increase], and corrected to 8-hr ozone using the reported ratio between daily 8-hr and 24-hr average ozone associations with nonaccidental mortality. Using these methods, we estimated 362,000 (95% confidence interval, 173,000–551,000) annual global premature cardiopulmonary deaths attributable to ozone, approximately 50% of the 700,000 premature deaths we calculated in our original study (Anenberg et al. 2010). Since estimated deaths due to PM2.5 (3.7 million) are an order of magnitude larger, using a short-term rather than long-term RR estimate for ozone has only a minor effect on the overall global burden of disease due to outdoor air pollution. As RRs for chronic ozone mortality are not as strongly supported as those for PM2.5, we expect that estimates of mortality burden will improve as research on chronic ozone exposure and mortality continues globally.

Biomarkers of lung‐related diseases: Current knowledge by proteomic approaches

The lung epithelial surface is one of the vital barriers or sensors in the body responding to the external atmosphere and thereby always subjecting to direct toxicological exposure, stress, stimulus, or infection. Due to its relatively higher sensitivity in response to toxicants, the use of lung epithelial cell culture and lung tissue from animal models or patients has facilitated our learning to lung physiopathology and toxicopharmacology. The recent advancement of proteomics has made it possible to investigate the cellular response at a global level. In this review, the potential applications of proteomic approach in studying lung‐related diseases and biomarker discovery will be discussed. J. Cell. Physiol. 221: 535–543, 2009. © 2009 Wiley‐Liss, Inc.

Human Exposure to Selected Animal Neurocarcinogens: A Biomarker-Based Assessment and Implications for Brain Tumor Epidemiology

This review is based on the proceedings from the Second Lebow Conference, held in Chicago in 2007. The conference concentrated on developing a framework for innovative studies in the epidemiology of environmental exposures, focusing specifically on the potential relationship with brain tumors. Researchers with different perspectives, including toxicology, pharmacokinetics, and epidemiological exposure assessment, exchanged information and ideas on the use of biomarkers of exposure in molecular epidemiology studies and summarized the current knowledge on methods and approaches for biomarker-based exposure assessment. This report presents the state of science regarding biomarker-based exposure assessment of the four most common neurocarcinogens: acrylamide, 1,3-butadiene, N-nitroso compounds, and polycyclic aromatic hydrocarbons. Importantly, these chemicals are also carcinogenic in other organs; therefore, this discussion is useful for environmental epidemiologists studying all cancer types.

Current developments in reproductive toxicity testing of pesticides

A protocol to evaluate the potential developmental and reproductive effects of test chemicals has been developed by the Life Stages Task Force of the International Life Sciences Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical Safety Assessment (ACSA) Technical Committee. Since the original publication, several international groups have provided public comment on conducting the test. The extended one-generation reproductive toxicity test is now under consideration as a potential test guideline. The protocol uses a flexible approach that is markedly different from the current multigenerational guidelines. It encourages the use of toxicokinetics when setting the doses, evaluates more than one rat per sex per litter in the F1 offspring and does not necessarily require mating of the F1 to produce an F2 (F1 mating may be triggered by the presence of effects in the P0 and developing F1 rats). A number of additional reproductive endpoints, and the neurotoxicity and immunotoxicity cohorts are included. The ACSA protocol was developed with the goal of assuring that the methods are scientifically appropriate and the toxicological endpoints and exposure durations are relevant for risk assessment. Compared to existing testing strategies, the proposed approach uses substantially fewer animals, provides additional information on the neonate, juvenile and pubertal animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required. In this paper, the evolution of the protocol since the 2006 publication is discussed. These changes reflect the collective input of a U.S. expert panel of government and industrial scientist convened in 2007 and discussions of an OECD expert group held in Paris, France (October, 2008).