Occupational exposure to antimony trioxide: a risk assessment.

OBJECTIVES: The US National Toxicology Program (NTP) recently recommended in its Report on Carcinogens Monograph for Antimony Trioxide that antimony trioxide be listed as 'reasonably anticipated to be a human carcinogen' based on sufficient evidence of carcinogenicity in experimental animals and supporting evidence from mechanistic studies. Our goal was to estimate the possible human cancer risk from occupational exposure to antimony trioxide. METHODS: We selected data from 2-year inhalation studies in male and female mice conducted by the NTP and performed cancer dose-response analyses using cancer models and benchmark dose methods developed by the US Environmental Protection Agency. In these analyses, we generated benchmark doses and cancer slope factors for antimony trioxide, and then estimated human cancer risk under various exposure scenarios. Typical and worst-case inhalation scenarios in multiple occupational settings were used in risk estimation. RESULTS: In typical case scenarios, the occupational cancer risk from antimony trioxide was estimated to be 0.025 (25 in 1000) for persons working with flame retardants in plastics and textiles for 40 years. Under worst-case scenarios, the occupational cancer risk was estimated to be 0.11 (110 in 1000) for persons working with flame retardants in plastics and textiles. At the current Occupational Safety and Health Administration Permissible Exposure Limit, the cancer risk for occupational inhalation exposure of antimony trioxide was estimated to be 0.096 (96 in 1000). CONCLUSION: The risk estimates calculated in this study suggest that exposure to antimony trioxide at levels present in certain occupational settings results in a large increase in the risk of developing cancer.

Plasma glucocorticogenic activity, race/ethnicity and alcohol intake among San Francisco Bay Area women.

Racial and ethnic minorities are at higher risk for a variety of diseases. While sociodemographic and lifestyle factors contribute to racial/ethnic health disparities, the biological processes underlying these associations remain poorly understood. Stress and its biological consequences through the glucocorticoid receptor (GR) have been hypothesized to mediate adverse disease outcomes. In fasting morning samples of 503 control women from the San Francisco Bay Area Breast Cancer Study, we used a sensitive Chemical-Activated LUciferase gene eXpression (CALUX) assay to examine the association of sociodemographic and lifestyle factors with plasma glucocorticogenic (G) activity in three racial/ethnic groups. The G activity is a sensitive measure that reflects biological activity of total plasma glucocorticoids including cortisol and glucocorticoid-like compounds. Associations between G activity and sociodemographic and lifestyle factors were examined using multivariable linear regression models. Latina and non-Latina Black (NLB) women had 9% (P = 0.053) and 14% (P = 0.008) lower morning G activity than non-Latina White (NLW) women, respectively. Additionally, we replicated a previously reported association between G activity and alcohol intake (women who drank >10gms had 19% higher G activity than non-drinkers, P = 0.004) in Latina and NLB women. Further research should assess the association between G activity and health outcomes in a prospective cohort so as to characterize the relationship between total plasma G activity in pre-disease state and disease outcomes across different racial/ethnic populations.

Proposed Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment.

BACKGROUND: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and in vivo toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking. OBJECTIVE: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification. METHODS: A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell­cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways; and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics. DISCUSSION: Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use. https://doi.org/10.1289/EHP4971.

Socioeconomic status and the association between arsenic exposure and type 2 diabetes.

OBJECTIVE: Evaluate whether arsenic-related diabetes risks differ between people of low and high socioeconomic status (SES). METHODS: We used data collected between October 2007-December 2010 from a population-based cancer case-control study (N = 1301) in Northern Chile, an area with high arsenic water concentrations (>800 µg/L) and comprehensive records of past exposure. Information on lifetime exposure and potential confounders were obtained using structured interviews, questionnaires, and residential histories. Type 2 diabetes was defined as physician-diagnosed diabetes or oral hypoglycemic medication use. SES was measured using a 14-point scale based on ownership of household appliances, cars, internet access, or use of domestic help. Logistic regression was used to assess the relationship between arsenic and diabetes within strata of SES. RESULTS: Among those with low SES, the odds ratio (OR) for diabetes comparing individuals in the highest to lowest tertile of lifetime average arsenic exposure was 2.12 (95% confidence interval (CI) 1.29-3.49, p = 0.004). However, those in the high SES group were not at increased risk (OR = 1.12 [95% CI = 0.72-1.73]). CONCLUSIONS: Our findings provide evidence that risks of arsenic-related diabetes may be higher in Chile in people with low versus high SES.

Assessment of the Endocrine-Disrupting Effects of Trichloroethylene and Its Metabolites Using in Vitro and in Silico Approaches.

Trichloroethylene (TCE) is a ubiquitous environmental contaminant, which may have effects on both ecosystem and human health. TCE has been reported to cause several toxic effects, but little effort has been made to assess the ecological risks of TCE or its major metabolites: trichloroethanol (TCOH), trichloroacetic acid, and oxalic acid (OA). In this study, the endocrine-disrupting potential of TCE and its metabolites were investigated using in vitro and in silico approaches. We examined alterations in the steroidogenesis pathway using the NCI-H295R cell line and utilized receptor-mediated luciferase reporter cell lines to identify effects on estrogen and androgen receptors. Molecular docking was also used to explore chemical interactions with these receptors. All test chemicals except OA significantly increased 17ß-estradiol production which can be attributed to an up-regulation of 17ß-hydroxysteroid dehydrogenase. Moreover, TCOH exhibited significant antiestrogenic activity with a RIC20 (20% relative inhibitory concentration) of 3.7 × 10-7 M. Molecular docking simulation supported this finding with lower docking scores for TCOH, indicating that hydrogen bonds may stabilize the interaction between TCOH and the estrogen receptor binding pocket. These findings suggest that TCE contamination poses an endocrine-disrupting threat, which has implications for both ecological and human health.

The Next Generation of Risk Assessment Multi-Year Study-Highlights of Findings, Applications to Risk Assessment, and Future Directions.

BACKGROUND: The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions. OBJECTIVE: Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures. METHODS: New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling. DISCUSSION: NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams. CONCLUSIONS: While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. Citation: Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study-highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671-1682; http://dx.doi.org/10.1289/EHP233.

Translational cancer research: balancing prevention and treatment to combat cancer globally.

Cancer research is drawing on the human genome project to develop new molecular-targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population-based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population.

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment.

Benzene causes acute myeloid leukemia and probably other hematological malignancies. As benzene also causes hematotoxicity even in workers exposed to levels below the US permissible occupational exposure limit of 1 part per million, further assessment of the health risks associated with its exposure, particularly at low levels, is needed. Here, we describe the probable mechanism by which benzene induces leukemia involving the targeting of critical genes and pathways through the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability, in a hematopoietic stem cell (HSC); stromal cell dysregulation; apoptosis of HSCs and stromal cells and altered proliferation and differentiation of HSCs. These effects modulated by benzene-induced oxidative stress, aryl hydrocarbon receptor dysregulation and reduced immunosurveillance, lead to the generation of leukemic stem cells and subsequent clonal evolution to leukemia. A mode of action (MOA) approach to the risk assessment of benzene was recently proposed. This approach is limited, however, by the challenges of defining a simple stochastic MOA of benzene-induced leukemogenesis and of identifying relevant and quantifiable parameters associated with potential key events. An alternative risk assessment approach is the application of toxicogenomics and systems biology in human populations, animals and in vitro models of the HSC stem cell niche, exposed to a range of levels of benzene. These approaches will inform our understanding of the mechanisms of benzene toxicity and identify additional biomarkers of exposure, early effect and susceptibility useful for risk assessment.

Assessment of genetic damage in healthy and diseased tissue.

DNA, along with other cellular components, is under constant attack by chemical, physical, and infectious agents present in the human environment, as well as by reactive metabolites generated by physiological processes. Mutations occur as the consequence of this damage, but may also be caused by improper DNA repair of alterations occurring during normal DNA replication and transcription. Genetic damage can occur at the level of the gene (e.g. point mutations, insertions, and deletions) or at the level of the chromosome (e.g. aneuploidy, translocations). Further, mutations can also take place in mitochondrial DNA. Another form of DNA modification is epigenetic methylation of CpG islands, which affects the dynamics of chromatin as well as the expression of a large panel of genes. Recent technical advances have improved the capacity to detect and quantify genetic and epigenetic changes. This chapter summarizes current knowledge on mechanisms of DNA damage and mutagenesis, laying out the concepts for interpreting mutations as biomarkers in investigating the causes and consequences of cancer. It also outlines both established and novel methods for detecting genetic and epigenetic changes in normal and diseased tissues, and then discusses their application in the realm of molecular epidemiology.

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).

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.

Formaldehyde in China: production, consumption, exposure levels, and health effects.

Formaldehyde, an economically important chemical, is classified as a human carcinogen that causes nasopharyngeal cancer and probably leukemia. As China is the largest producer and consumer of formaldehyde in the world, the Chinese population is potentially at increased risk for cancer and other associated health effects. In this paper we review formaldehyde production, consumption, exposure, and health effects in China. We collected and analyzed over 200 Chinese and English documents from scientific journals, selected newspapers, government publications, and websites pertaining to formaldehyde and its subsequent health effects. Over the last 20 years, China's formaldehyde industry has experienced unprecedented growth, and now produces and consumes one-third of the world's formaldehyde. More than 65% of the Chinese formaldehyde output is used to produce resins mainly found in wood products - the major source of indoor pollution in China. Although the Chinese government has issued a series of standards to regulate formaldehyde exposure, concentrations in homes, office buildings, workshops, public places, and food often exceed the national standards. In addition, there have been numerous reports of formaldehyde-induced health problems, including poisoning and cancer. The lack of quality epidemiological studies and basic data on exposed populations emphasizes the need for more extensive studies on formaldehyde and its related health effects in China.

Assessment of dermal exposure to benzene and toluene in shoe manufacturing by activated carbon cloth patches.

OBJECTIVES: The aim of this investigation was to use activated carbon cloth (ACC) patches to study the probability and extent of dermal exposure to benzene and toluene in a shoe factory. METHODS: Inhalation and dermal exposure loading were measured simultaneously in 70 subjects on multiple days resulting in 113 observations. Dermal exposure loading was assessed by ACC patches attached to likely exposed skin areas (e.g. the palm of the hand and abdomen). A control patch at the chest and an organic vapor monitor (OVM) were used to adjust the hand and abdomen patches for the contribution from the air through passive absorption of benzene and toluene on the ACC patches. Systemic exposure was assessed by quantification of unmetabolized benzene (UBz) and toluene (UTol) in urine. RESULTS: Mean air concentrations for the study population were 1.5 and 7.5 ppm for benzene and toluene, respectively. Iterative regression analyses between the control patch, OVM and the dermal patches showed that only a small proportion of the ACC patches at the hand had likely benzene (n = 4; mean 133 microg cm(-2) h(-1)) or toluene (n = 5; mean 256 microg cm(-2) h(-1)) contamination. Positive patches were exclusively observed among subjects performing the task of gluing. Significant dermal exposure loading to the abdomen was detected only for toluene (n = 2; mean 235 microg cm(-2) h(-1)). No relation was found between having a positive hand or abdomen ACC patch and UBz or UTol levels. In contrast a strong association was found between air levels of benzene (p = 0.0016) and toluene (p < 0.0001) and their respective urinary levels. CONCLUSIONS: ACC patches are shown to be a useful technique for quantifying the probability of dermal exposure to organic solvents and to provide estimates of the potential contribution of the dermal pathway to systemic exposure. Using ACC patches we show that dermal exposure to benzene and toluene in a shoe manufacturing factory is probably rare, and when it occurred exposures were relatively low and did not significantly contribute to systemic exposure.

Personalized exposure assessment: promising approaches for human environmental health research.

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a "toolbox" of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure-disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs.

Detailed exposure assessment for a molecular epidemiology study of benzene in two shoe factories in China.

OBJECTIVES: We carried out a detailed exposure assessment of benzene and toluene in two shoe factories in Tianjin, China. Our goal was to identify workers with a broad range of benzene exposures, for an epidemiologic study relating exposure to early biologic effects. METHODS: A comprehensive exposure survey program was initiated. Over a period of 16 months, 2783 personal solvent exposure samples were collected in two workplaces from 250 workers. Mixed-effects models were used to identify factors affecting exposure. Principal component analyses (PCA) and subsequent regression analyses on the scores of the identified principal components were used to relate potential co-exposures to various exposure sources present in the workplace. RESULTS: The mean benzene exposure level was 21.86 p.p.m. (10th-90th percentiles 5.23-50.63 p.p.m.) in the smaller shoe factory (factory A) and 3.46 p.p.m. (10th-90th percentiles 0.20-7.00 p.p.m.) in the larger shoe factory (factory B). Within-factory exposure levels differed among job titles and were higher for subjects directly involved in handling glues. In contrast, mean toluene levels were relatively similar in the two factories (factory A, 9.52 p.p.m.; factory B, 15.88 p.p.m.). A seasonal trend was identified for both benzene and toluene in factory B. This could be explained in part by changes in air movement and ventilation patterns occurring during the year. A seasonal trend was not present in the smaller shoe factory, where general ventilation was absent. Supplemental analysis showed that exposure levels to other hydrocarbons were low (< or =5 p.p.m.), less than 5% of their respective ACGIH threshold limit values, and generally comparable in the two factories. PCA showed that co-exposures in factory B could largely be explained by glue sources that were used in distinct areas in the workplace. CONCLUSIONS: We demonstrated the occurrence of a broad range of benzene exposure levels in two shoe manufacturing factories in Tianjin, China. Benzene and toluene exposures were determined in part by the degree of contact with glues, the benzene and toluene content of each glue, air movement and ventilation patterns. The availability of long-term monthly personal monitoring data provides an excellent opportunity to estimate individual exposures at different times during the 1 yr period of observation.

The use of non-tumor data in cancer risk assessment: reflections on butadiene, vinyl chloride, and benzene.

The estimation and characterization of a cancer risk is grounded in the observation of tumors in humans and/or experimental animals. Increasingly, however, other kinds of data (non-tumor data) are finding application in cancer risk assessment. Metabolism and kinetics, adduct formation, genetic damage, mode of action, and biomarkers of exposure, susceptibility, and effects are examples. While these and other parameters have been studied for many important chemicals over the past 30-40 years, their use in risk assessments is more recent, and new insights and opportunities are continuing to unfold. To provide some perspective on this field, the ILSI Risk Science Institute asked a select working group to characterize the pertinent non-tumor data available for 1,3-butadiene, benzene, and vinyl chloride and to comment on the utility of these data in characterizing cancer risks. This paper presents the findings of that working group and concludes with 15 simple principles for the use of non-tumor data in cancer risk assessment.