AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility.

BACKGROUND: Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations. OBJECTIVE: To examine the impact of genotypic polymorphisms on iAs metabolism. METHODS: We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration. RESULTS: In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism. DISCUSSION: Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs. CONCLUSIONS: Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility.

Cancer in experimental animals exposed to arsenic and arsenic compounds.

Inorganic arsenic is a ubiquitous environmental contaminant that has long been considered a human carcinogen. Recent studies raise further concern about the metalloid as a major, naturally occurring carcinogen in the environment. However, during this same period it has proven difficult to provide experimental evidence of the carcinogenicity of inorganic arsenic in laboratory animals and, until recently, there was considered to be a lack of clear evidence for carcinogenicity of any arsenical in animals. More recent work with arsenical methylation metabolites and early life exposures to inorganic arsenic has now provided evidence of carcinogenicity in rodents. Given that tens of millions of people worldwide are exposed to potentially unhealthy levels of environmental arsenic, in vivo rodent models of arsenic carcinogenesis are a clear necessity for resolving critical issues, such as mechanisms of action, target tissue specificity, and sensitive subpopulations, and in developing strategies to reduce cancers in exposed human populations. This work reviews the available rodent studies considered relevant to carcinogenic assessment of arsenicals, taking advantage of the most recent review by the International Agency for Research on Cancer (IARC) that has not yet appeared as a full monograph but has been summarized (IARC, 2009 , IARC Special Report: Policy, Vol. 10. Lyon: IARC Press, 453­454). Many valid studies show that arsenic can interact with other carcinogens/agents to enhance oncogenesis, and help elucidate mechanisms, and these too are summarized in this review. Finally, this body of rodent work is discussed in light of its impact on mechanisms and in the context of the persistent argument that arsenic is not carcinogenic in animals.

Novel text analytics approach to identify relevant literature for human health risk assessments: A pilot study with health effects of in utero exposures.

BACKGROUND: Systematic reviews involve mining literature databases to identify relevant studies. Identifying potentially relevant studies can be informed by computational tools comparing text similarity between candidate studies and selected key (i.e., seed) references. Challenge Using computational approaches to identify relevant studies for risk assessments is challenging, as these assessments examine multiple chemical effects across lifestages (e.g., human health risk assessments) or specific effects of multiple chemicals (e.g., cumulative risk). The broad scope of potentially relevant literature can make selection of seed references difficult. Approach We developed a generalized computational scoping strategy to identify human health relevant studies for multiple chemicals and multiple effects. We used semi-supervised machine learning to prioritize studies to review manually with training data derived from references cited in the hazard identification sections of several US EPA Integrated Risk Information System (IRIS) assessments. These generic training data or seed studies were clustered with the unclassified corpus to group studies based on text similarity. Clusters containing a high proportion of seed studies were prioritized for manual review. Chemical names were removed from seed studies prior to clustering resulting in a generic, chemical-independent method for identifying potentially human health relevant studies. We developed a case study that focused on identifying the array of chemicals that have been studied with respect to in utero exposure to test the recall of this novel literature searching strategy. We then evaluated the general strategy of using generic, chemical-independent training data with two previous IRIS assessments by comparing studies predicted relevant to those used in the assessments (i.e., total relevant). Outcome A keyword search designed to retrieve studies that examined the in utero effects of environmental chemicals identified over 54,000 candidate references. Clustering algorithms were applied using 1456 studies from multiple IRIS assessments with chemical names removed as training data or seeds (i.e., semi-supervised learning). Using a six-algorithm ensemble approach 2602 articles, or approximately 5% of candidate references, were "voted" relevant by four or more clustering algorithms and manual review confirmed nearly 50% of these studies were relevant. Further evaluations on two IRIS assessments, using a nine-algorithm ensemble approach and a set of generic, chemical-independent, externally-derived seed studies correctly identified 77-83% of hazard identification studies published in the assessments and eliminated the need to manually screen more than 75% of search results on average. Limitations The chemical-independent approach used to build the training literature set provides a broad and unbiased picture across a variety of endpoints and environmental exposures but does not systematically identify all available data. Variance between actual and predicted relevant studies will be greater because of the external and non-random origin of seed study selection. This approach depends on access to readily available generic training data that can be used to locate relevant references in an unclassified corpus. Impact A generic approach to identifying human health relevant studies could be an important first step in literature evaluation for risk assessments. This initial scoping approach could facilitate faster literature evaluation by focusing reviewer efforts, as well as potentially minimize reviewer bias in selection of key studies. Using externally-derived training data has applicability particularly for databases with very low search precision where identifying training data may be cost-prohibitive.

A Chemical Category-Based Prioritization Approach for Selecting 75 Per- and Polyfluoroalkyl Substances (PFAS) for Tiered Toxicity and Toxicokinetic Testing.

Per- and polyfluoroalkyl substances (PFASs) are a group of fluorinated substances of interest to researchers, regulators, and the public due to their widespread presence in the environment. A few PFASs have comparatively extensive amounts of human epidemiological, exposure, and experimental animal toxicity data (e.g., perfluorooctanoic acid), whereas little toxicity and exposure information exists for much of the broader set of PFASs. Given that traditional approaches to generate toxicity information are resource intensive, new approach methods, including in vitro high-throughput toxicity (HTT) testing, are being employed to inform PFAS hazard characterization and further (in vivo) testing. The U.S. Environmental Protection Agency (EPA) and the National Toxicology Program (NTP) are collaborating to develop a risk-based approach for conducting PFAS toxicity testing to facilitate PFAS human health assessments. This article describes the construction of a PFAS screening library and the process by which a targeted subset of 75 PFASs were selected. Multiple factors were considered, including interest to the U.S. EPA, compounds within targeted categories, structural diversity, exposure considerations, procurability and testability, and availability of existing toxicity data. Generating targeted HTT data for PFASs represents a new frontier for informing priority setting. https://doi.org/10.1289/EHP4555.

The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency.

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA's Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.

Relationships between arsenic concentrations in drinking water and lung and bladder cancer incidence in U.S. counties.

Increased risks of lung and bladder cancer have been observed in populations exposed to high levels of inorganic arsenic. However, studies at lower exposures (i.e., less than 100 µg/l in water) have shown inconsistent results. We therefore conducted an ecological analysis of the association between historical drinking water arsenic concentrations and lung and bladder cancer incidence in U.S. counties. We used drinking water arsenic concentrations measured by the U.S. Geological Survey and state agencies in the 1980s and 1990s as proxies for historical exposures in counties where public groundwater systems and private wells are important sources of drinking water. Relationships between arsenic levels and cancer incidence in 2006-2010 were explored by Poisson regression analyses, adjusted for groundwater dependence and important demographic covariates. The median and 95th percentile county mean arsenic concentrations were 1.5 and 15.4 µg/l, respectively. Water arsenic concentrations were significant and positively associated with female and male bladder cancer, and with female lung cancer. Our findings support an association between low water arsenic concentrations and lung and bladder cancer incidence in the United States. However, the limitations of the ecological study design suggest caution in interpreting these results.

Systematic review of differential inorganic arsenic exposure in minority, low-income, and indigenous populations in the United States.

Inorganic arsenic (iAs) is a human carcinogen and associated with cardiovascular, respiratory, and skin diseases. Natural and anthropogenic sources contribute to low concentrations of iAs in water, food, soil, and air. Differential exposure to environmental hazards in minority, indigenous, and low income populations is considered an environmental justice (EJ) concern, yet it is unclear if higher iAs exposure occurs in these populations. A systematic review was conducted to evaluate evidence for differential iAs exposure in the United States (US). The peer-reviewed literature was searched for studies that (1) estimated iAs exposure based on environmental concentrations of iAs in water, food, soil, or iAs biomarkers and (2) examined iAs exposure in minority, indigenous, and low income US populations. Five studies were identified that estimated exposures and provided demographic information about EJ populations. These studies reported arsenic concentrations in water, soil, or food to estimate exposure, with varied evidence of differential exposure. Additionally, six studies were identified that suggested potential arsenic exposure from environmental sources including soil, rice, private well-water, and fish, but did not report data stratified by demographic information. Evidence across these 11 studies was qualitatively integrated to draw conclusions about differential iAs exposure. The total body of evidence is limited by lack of individual exposure measures, lack of iAs concentration data, and insufficient comparative demographic data. Based upon these data gaps, there is inadequate evidence to conclude whether differential exposure to iAs is an EJ concern in the US.

Utility of recent studies to assess the National Research Council 2001 estimates of cancer risk from ingested arsenic.

OBJECTIVE: The purpose of this review is to evaluate the impact of recent epidemiologic literature on the National Research Council (NRC) assessment of the lung and bladder cancer risks from ingesting low concentrations (< 100 µg/L) of arsenic-contaminated water. DATA SOURCES, EXTRACTION, AND SYNTHESIS: PubMed was searched for epidemiologic studies pertinent to the lung and bladder cancer risk estimates from low-dose arsenic exposure. Articles published from 2001, the date of the NRC assessment, through September 2010 were included. Fourteen epidemiologic studies on lung and bladder cancer risk were identified as potentially useful for the analysis. CONCLUSIONS: Recent epidemiologic studies that have investigated the risk of lung and bladder cancer from low arsenic exposure are limited in their ability to detect the NRC estimates of excess risk because of sample size and less than lifetime exposure. Although the ecologic nature of the Taiwanese studies on which the NRC estimates are based present certain limitations, the data from these studies have particular strengths in that they describe lung and bladder cancer risks resulting from lifetime exposure in a large population and remain the best data on which to conduct quantitative risk assessment. Continued follow-up of a population in northeastern Taiwan, however, offers the best opportunity to improve the cancer risk assessment for arsenic in drinking water. Future studies of arsenic < 100 µg/L in drinking water and lung and bladder cancer should consider adequacy of the sample size, the synergistic relationship of arsenic and smoking, duration of arsenic exposure, age when exposure began and ended, and histologic subtype.

Development of a quantitative model incorporating key events in a hepatotoxic mode of action to predict tumor incidence.

Biologically based dose-response (BBDR) modeling of environmental pollutants can be utilized to inform the mode of action (MOA) by which compounds elicit adverse health effects. Chemicals that produce tumors are typically labeled as either genotoxic or nongenotoxic. Though both the genotoxic and the nongenotoxic MOA may be operative as a function of dose, it is important to note that the label informs but does not define a MOA. One commonly proposed MOA for nongenotoxic carcinogens is characterized by the key events cytotoxicity and regenerative proliferation. The increased division rate associated with such proliferation can cause an increase in the probability of mutations, which may result in tumor formation. We included these steps in a generalized computational pharmacodynamic (PD) model incorporating cytotoxicity as a MOA for three carcinogens (chloroform, CHCl(3); carbon tetrachloride, CCL(4); and N,N-dimethylformamide, DMF). For each compound, the BBDR model is composed of a chemical-specific physiologically based pharmacokinetic model linked to a PD model of cytotoxicity and cellular proliferation. The rate of proliferation is then linked to a clonal growth model to predict tumor incidences. Comparisons of the BBDR simulations and parameterizations across chemicals suggested that significant variation among the models for the three chemicals arises in a few parameters expected to be chemical specific (such as metabolism and cellular injury rate constants). Optimization of model parameters to tumor data for CCL(4) and DMF resulted in similar estimates for all parameters related to cytotoxicity and tumor incidences. However, optimization of the CHCl(3) data resulted in a higher estimate for one parameter (BD) related to death of initiated cells. This implies that additional steps beyond cytotoxicity leading to induced cellular proliferation can be quantitatively different among chemicals that share cytotoxicity as a hypothesized carcinogenic MOA.

Workshop overview: arsenic research and risk assessment.

The chronic exposure of humans through consumption of high levels of inorganic arsenic (iAs)-contaminated drinking water is associated with skin lesions, peripheral vascular disease, hypertension, and cancers. Additionally, humans are exposed to organic arsenicals when used as pesticides and herbicides (e.g., monomethylarsonic acid, dimethylarsinic acid (DMA(V)) also known as cacodylic acid). Extensive research has been conducted to characterize the adverse health effects that result from exposure to iAs and its metabolites to describe the biological pathway(s) that lead to adverse health effects. To further this effort, on May 31, 2006, the United States Environmental Protection Agency (USEPA) sponsored a meeting entitled "Workshop on Arsenic Research and Risk Assessment". The invited participants from government agencies, academia, independent research organizations and consultants were asked to present their current research. The overall focus of these research efforts has been to determine the potential human health risks due to environmental exposures to arsenicals. Pursuant in these efforts is the elucidation of a mode of action for arsenicals. This paper provides a brief overview of the workshop goals, regulatory context for arsenical research, mode of action (MOA) analysis in human health risk assessment, and the application of MOA analysis for iAs and DMA(V). Subsequent papers within this issue will present the research discussed at the workshop, ensuing discussions, and conclusions of the workshop.

Effects of alpha- and beta-hydroxy acids on the edemal response induced in female SKH-1 mice by simulated solar light.

alpha- and beta-Hydroxy acids have been used extensively in cosmetic and dermatological formulations. At present, there is an inadequate amount of information with which to assess the safety of topical applications of alpha- and beta-hydroxy acids in conjunction with exposure to ultraviolet light. In the present study, we examined changes in the epidermal basal cell proliferation and the edemal response using skin thickness measurements elicited in SKH-1 mice following exposure to simulated solar light (SSL) with or without topical treatment with creams containing alpha- (glycolic) and beta-hydroxy (salicylic) acids. The dose of SSL light required to induce measurable edema (MED(BIOL)) in nai;ve, free-moving SKH-1 mice was determined to be 90 mJ. CIE/cm(2). Pretreating the mice with daily (5 days/week) exposures of 14 mJ. CIE/cm(2) for 6 weeks resulted in a doubling of the MED(BIOL) to 180 mJ. CIE/cm(2). Topical application of control cream (pH 3.5), or creams containing glycolic acid (10%, pH 3.5) or salicylic acid (4%, pH 3.5) for 6 weeks (5 days/week) increased the MED(BIOL) to 137 mJ. CIE/cm(2). Daily treatments with SSL (14 mJ. CIE/cm(2)) and control cream (pH 3.5), glycolic (10%, pH 3.5) or salicylic (4%, pH 3.5) acid-containing creams for 6 weeks (5 days/week) resulted in an MED(BIOL) value of 180 mJ. CIE/cm(2), which was the same as treatment with light alone for 6 weeks. These data indicate that a 6-week treatment of mouse skin with a representative skin cream, with or without representative alpha- and beta-hydroxy acids (glycolic and salicylic acid, respectively), changes the UV light sensitivity; however, treatment with the cream, with or without the acids, does not contribute to the UV sensitivity of mice cotreated with low doses of UV light.