Manganese (Mn) plays a dual role in the body, acting as an essential trace element and a potential toxicant, the effects of which depend on its levels. In addition to food, exposure can occur through polluted air and contaminated water. Animal studies suggest that increased retention and absorption of Mn might result from iron deficiency, as both share similar physicochemical properties. However, human evidence is incomplete. This study aimed to confirm and expand upon prior findings that iron status influences Mn kinetics in the U.S. female population. The analysis included 1255 non-pregnant females aged 12-49 years with valid urinary and blood Mn and iron measurements as part of the 2015-2018 National Health and Nutrition Examination Survey. Iron status was assessed with a total body iron (TBI) score calculated from measured serum ferritin and the transferrin receptor. Iron deficiency was defined as a TBI score < 0. Demographic and laboratory characteristics (e.g. age and kidney function) were recorded. Among the study participants, roughly 8.8% were found to have iron deficiency. Conversely, 16.9% of participants exhibited blood Mn levels exceeding 1.5 µg/dL, a commonly used reference. On average, blood Mn was approximately 40% higher in subjects considered iron deficient than in their counterparts after controlling for covariates such as race. Those with iron deficiency also had a lower urine-to-blood Mn ratio. The findings suggest that iron-deficient females may have greater Mn accumulation, increasing the risk of Mn toxicity. Further investigations should include male populations to complement the current findings.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with both systematic inflammation and renal dysfunction. Reports have suggested that anti-inflammatory properties of vitamin D may provide protection against renal injury. This cross-sectional study tested the hypothesis that serum 25-hydroxyvitamin D [25(OH)D] moderates the inflammation and albuminuria associated with PAH exposure. Data were obtained from 5,982 subjects aged 20-79 years in the National Health and Nutrition Examination Survey (2001-2010). PAH exposure was estimated by urinary PAH metabolites. Inflammation was defined as serum C-reactive protein (CRP) > 3 mg/L and albuminuria as urinary albumin-to-creatinine ratio > 30 mg/g. The results found that greater PAH exposure was linked with inflammation and albuminuria. Individuals with PAH exposure also tended to have lower 25(OH)D and lower vitamin D was associated with both elevated CRP (Odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.07-1.54) and urinary albumin (1.35, 95%CI = 1.03-1.77) for any given PAH exposure. Those with lower serum 25(OH)D-to-urinary PAH ratios were likewise at a greater risk of elevated CRP and albuminuria. The findings support prior suggestions that exposure to PAHs is associated with inflammation and albuminuria but suggests further that the risk is higher when vitamin D is lower. Thus, nutritional status becomes an important variable in PAH risk assessment.

Abstract As global demand for electronic products rises, it also generates a significant volume of e‐waste at an alarming rate. E‐waste recycling and disposal are one of the world's fastest‐growing pollution problems, with an estimated 53 million metric tons produced in 2019 and a raw material value of $57 billion. It is expected to reach 74.7 million metric tons by 2030. Developed countries generate most of the world's e‐waste and export it to low‐income Asian and African countries. Managing e‐waste, both domestically generated and imported, is a major environmental health issue in developing countries. Recycling electronic waste recovers precious metals and resalable parts to generate revenue. E‐waste and its recycling practices release a variety of known hazardous chemicals such as Pb, Hg, Cd, hexavalent Cr, brominated flame retardants (BFRs), polybrominated diphenyl ethers (PBDs), poly‐brominated/chlorinated biphenyls (PBBs/PCBs), polychlorinated dibenzodioxins/dibenzofurans (PCDDs/PCDFs), polyaromatic hydrocarbons (PAHs), and other chemicals. Developing countries lack adequate analytical laboratory resources and methods to measure the exposure of these toxic pollutants in air, water, food, and soil during recycling/disposal practices. Analytical data are critical to perform chemical exposure assessment for aggregate and cumulative risk assessment to exposed people, especially vulnerable populations (women and children) involved in handling and recycling operations in developing countries. In addition, a brief description of approaches to minimize risks, raising awareness of the problem of informal e‐waste management, and international efforts, policies, and regulations of the e‐waste legislation discussed.

AbstractThis chapter primarily focuses on the human health effects of formaldehyde inhalation exposure. It summarizes significant published findings and recently peer‐reviewed health risk assessments of national and international organizations on formaldehyde exposure including current regulatory standards.Formaldehyde is a flammable gas at room temperature and is found in consumer products and used in manufacturing processes, such as resins in composite wood products. Environmental exposure to formaldehyde can occur via inhalation, dermal, and ingestion routes. The most common route of formaldehyde exposure is inhalation resulting from breathing formaldehyde‐contaminated air. Formaldehyde enters the environment from natural and anthropogenic combustion sources, industrial on‐site releases, and off‐gassing of products containing formaldehyde. Acute and chronic exposures to formaldehyde through home furnishings, environmental contamination, cosmetics, and indoor and outdoor air pollution poses potential public health risks. Epidemiological, clinical, and experimental animal studies have shown that formaldehyde exposures are associated with potentially adverse human noncancer health outcomes. The epidemiologic evidence has shown an association between formaldehyde exposure and nasopharyngeal cancer as causal in human studies. Positive associations between formaldehyde exposure and lymphohematopoietic cancers have been reported for chemical workers, embalmers, anatomists, and pathologists. The mode(s) or mechanism(s) of formaldehyde exposure and reported cancers are not well understood; however, its exposure has been shown to be associated with the key events related to carcinogenicity.

Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child–adult differences in internal dose for a number of these chemicals.

Knowledge of the ontogeny of Phase I and Phase II metabolizing enzymes may be used to inform children's vulnerability based upon likely differences in internal dose from xenobiotic exposure. This might provide a qualitative assessment of toxicokinetic (TK) variability and uncertainty pertinent to early lifestages and help scope a more quantitative physiologically based toxicokinetic (PBTK) assessment. Although much is known regarding the ontogeny of metabolizing systems, this is not commonly utilized in scoping and problem formulation stage of human health risk evaluation. A framework is proposed for introducing this information into problem formulation which combines data on enzyme ontogeny and chemical-specific TK to explore potential child/adult differences in internal dose and whether such metabolic differences may be important factors in risk evaluation. The framework is illustrated with five case study chemicals, including some which are data rich and provide proof of concept, while others are data poor. Case studies for toluene and chlorpyrifos indicate potentially important child/adult TK differences while scoping for acetaminophen suggests enzyme ontogeny is unlikely to increase early-life risks. Scoping for trichloroethylene and aromatic amines indicates numerous ways that enzyme ontogeny may affect internal dose which necessitates further evaluation. PBTK modeling is a critical and feasible next step to further evaluate child-adult differences in internal dose for a number of these chemicals.

This chapter provides approaches for addressing the issues, thus making pharmacokinetic factors in early life amenable to being included in human health risk assessments. There are a number of behavioral, dietary, anatomical, and physiological factors that can cause children to be more highly exposed to environmental toxicants than adults. Among the factors are pharmacokinetic differences that can cause children, especially early in life, to have increased uptake and reduced clearance of chemicals. Some of the pharmacokinetic differences can be attributed to body size and composition while others are due to functional immaturity of critical clearance systems. Even for children of exactly the same age, pharmacokinetic functions can vary due to interindividual differences in the rate at which hepatic and renal systems mature. Chemical dosimetry will likely differ across children's developmental stages and between children and adults. There are numerous differences in absorption, distribution, metabolism, and elimination, which could interplay to affect dosimetry in early life.

Recent research has demonstrated that nonchemical stressors may alter the toxicity from chemical exposures. This may have public health implications for low socioeconomic status (SES) communities that may be disproportionately exposed to toxic chemicals and various types of community and personal stressors. Nonchemical stressors may introduce an important source of variability that needs to be considered by risk assessors. Herein, we propose a framework for determining if a chemical-nonchemical interaction exists and, if so, options for incorporating interaction information into risk assessments. We use the increasingly recognized interaction between lead and psychosocial stress to illustrate the framework. We found that lead exposure occurs disproportionately in low SES groups that also tend to face high levels of psychosocial stress; that stress and lead both affect neurodevelopment and that this occurs via similar pathways involving the hypothalamic-pituitary axis. Further, several epidemiological and experimental studies have provided evidence for an interaction between lead and psychosocial stress. The implications of this interaction for risk assessment are also discussed.

The majority of mercury (Hg) exposure in the US population is from consumption of fish contaminated with methylmercury (MeHg). Since inorganic Hg is the predominant form excreted in the feces and urine, hepatic biotransformation is a critical step in its normal clearance. This study was set to test the hypothesis that compromised liver function is associated with body burden of Hg as indirectly reflected by Hg sampled in blood and urine. From the National Health and Nutrition Examination Survey (NHANES, 2003-2008), 3769 adults aged 20 years and above were selected for analysis. Hepatic function was inferred from the three standard serum liver-related enzyme activities, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT). Multivariate regression models were used to examine the associations of interest. Although urinary Hg was significantly correlated with serum Hg, the blood-urinary Hg relationship was influenced by liver function, which is also a function of demographic and lifestyle factors (e.g., gender). Although the results were only marginally significant for examined enzymes (p=0.06-0.08), urinary Hg tended to be lower among subjects with elevated liver enzymes, as compared to those with normal enzyme measurements. Conversely, MeHg generally represents a higher fraction of the total circulating Hg among those with elevated liver enzyme levels, especially among participants with elevations in all three enzymes (p=0.01). In conclusion, this population-based study identified an association between liver function, serum Hg and urinary Hg. Urinalysis may not be the optimal approach to monitor Hg elimination toxicokinetics or Hg exposure, since the majority of Hg excretion is fecal and the fidelity of urinary excretion may depend on healthy liver function. Future prospective studies are warranted to expand these findings.

Numerous host and environmental factors may modulate vulnerability and risk. An area of increasing interest is the potential for chemicals to interact with background aging and disease processes, an interaction that may yield cumulative damage, altered chemical potency, and increased disease incidence. We evaluate the interactions possible between chemicals and background disease and identify the type of information needed to evaluate such interactions. Key among these is the existence of a clinically relevant and easy to measure biomarker of disease risk which is also modulated by a particular chemical of interest. This biomarker may be a physiological, biochemical, or genetic indicator that corresponds to a phase of the disease process and indicates where an individual is on the continuum between health and disease. The impact of toxic chemicals on this biomarker can then be used to predict how the chemical modifies disease risk, with this evidence strengthened by additional toxicology and epidemiology data showing toxicant effect on the disease process. Several case studies are presented which describe the toxic chemical, the clinical biomarker, the impacted disease and the evidence that the chemical enhances disease risk: fine particulate matter/decreased heart rate variability/increased cardiopulmonary events; cadmium/decreased glomerular filtration rate/increased chronic kidney disease; methyl mercury/decreased paraoxonase-1/increased cardiovascular risk; trichloroethylene/increased anti-nuclear antibody/autoimmunity; dioxin/increased CYP1A1/hypertension. These case studies point out that consideration of how a chemical interacts with background aging and disease processes may increase the public health relevance of risk assessment, identify important vulnerabilities, and provide new ways to calculate risk from exposure to environmental toxicants.

Understanding differential disease susceptibility requires new tools to quantify the cumulative effects of environmental stress. Evidence suggests that social, physical, and chemical stressors can influence disease through the accumulation of epigenetic modifications. Geographically stable epigenetic alterations could identify plausible mechanisms for health disparities among the disadvantaged and poor. Relations between neighborhood-specific epigenetic markers and disease would identify the most appropriate targets for medical and environmental intervention. Complex interactions among genes, the environment, and disease require the examination of how epigenetic changes regulate susceptibility to environmental stressors. Progress in understanding disparities in disease susceptibility may depend on assessing the cumulative effect of environmental stressors on genetic substrates. We highlight key concepts regarding the interface between environmental stress, epigenetics, and chronic disease.

Lymphohematopoietic neoplasia are one of the most common types of cancer induced by therapeutic and environmental agents. Of the more than 100 human carcinogens identified by the International Agency for Research on Cancer, approximately 25% induce leukemias or lymphomas. The objective of this review is to provide an introduction into the origins and mechanisms underlying lymphohematopoietic cancers induced by xenobiotics in humans with an emphasis on acute myeloid leukemia, and discuss the implications of this information for risk assessment. Among the agents causing lymphohematopoietic cancers, a number of patterns were observed. Most physical and chemical leukemia-inducing agents such as the therapeutic alkylating agents, topoisomerase II inhibitors, and ionizing radiation induce mainly acute myeloid leukemia through DNA-damaging mechanisms that result in either gene or chromosomal mutations. In contrast, biological agents and a few immunosuppressive chemicals induce primarily lymphoid neoplasms through mechanisms that involve alterations in immune response. Among the environmental agents examined, benzene was clearly associated with acute myeloid leukemia in humans, with increasing but still limited evidence for an association with lymphoid neoplasms. Ethylene oxide and 1,3-butadiene were linked primarily to lymphoid cancers. Although the association between formaldehyde and leukemia remains controversial, several recent evaluations have indicated a potential link between formaldehyde and acute myeloid leukemia. The four environmental agents examined in detail were all genotoxic, inducing gene mutations, chromosomal alterations, and/or micronuclei in vivo. Although it is clear that rapid progress has been made in recent years in our understanding of leukemogenesis, many questions remain for future research regarding chemically induced leukemias and lymphomas, including the mechanisms by which the environmental agents reviewed here induce these diseases and the risks associated with exposures to such agents.

Background: Despite animal evidence suggests that zinc modulates cadmium nephrotoxicity, limited human data are available.Objective: To test the hypothesis that low serum zinc concentrations may increase the risk of cadmium-mediated renal dysfunction in humans.Methods: Data from 1545 subjects aged 20 or older in the National Health and Nutrition Examination Survey (NHANES), 2011-2012 were analyzed. Renal function was defined as impaired when estimated glomerular filtration rate (eGFR) fell below 60 ml/min/1.73 m(2) and/or the urinary albumin-to-creatinine ratio surpassed 2.5 in men and 3.5 mg/mmol in women.Results: Within the study cohort, 117 subjects had reduced eGFR and 214 had elevated urinary albumin. After adjusting for potential confounders, subjects with elevated blood cadmium (> 0.53 mu g/L) were more likely to have a reduced eGFR (odds ratio [OR]=2.21, 95% confidence interval [CI]: 1.09-4.50) and a higher urinary albumin (OR=2.04, 95% CI: 1.13-3.69) than their low cadmium (< 0.18 mu g/L) peers. In addition, for any given cadmium exposure, low serum zinc is associated with elevated risk of reduced eGFR (OR=3.38, 95% CI: 1.39-8.28). A similar increase in the odds ratio was observed between declining serum zinc and albuminuria but failed to reach statistical significance. Those with lower serum zinc/blood cadmium ratios were likewise at a greater risk of renal dysfunction (p < 0.01).Conclusions: This study results suggest that low serum zinc concentrations are associated with an increased risk of cadmium nephrotoxicity. Elevated cadmium exposure is global public health issue and the assessment of zinc nutritional status may be an important covariate in determining its effective renal toxicity. Published by Elsevier Inc.

Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.

It remains unclear whether exposure to low-level mercury (Hg) is associated with impaired renal function, and whether omega-3 fatty acid (FA) intake could affect the association of interest. The current study examined the association of blood Hg and omega-3 FAs with renal function using data from 1046 subjects aged 40 or above from the 2003-2004 National Health and Nutrition Examination Survey. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and occurrence of albuminuria. Logistic regression analyses were applied to assess the association of interest with confounding variable adjustment. The analyses indicated that blood Hg was associated with reduced eGFR (<60mL/min/1.73m(2)) in a dose-response fashion (p<0.05). The association was particularly apparent with adjustment for blood omega-3 FA levels. The adjusted odds ratio for having reduced eGFR was 2.94 (95% confidence interval=1.04-8.33) in the highest tertile of blood Hg as compared with the lowest tertile. There was no significant association between Hg exposure and albuminuria. In summary, this study demonstrates that Hg exposure is associated with increased odds of having lower GFR in the US population aged 40 or above. A statistical association with albuminuria was not apparent. We also observed that omega-3 FA intake may play a preventive role in Hg-induced nephrotoxicity. Additional studies are warranted to determine the sources, exposure routes, and forms of Hg most responsible for observed associations.

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53(+/-), Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

Abstract The development of short-term or accelerated cancer bioassays using genetically modified (GM) animals that exhibit high sensitivity to chemically induced cancers and that act through mode(s) of action relevant to humans continues to be an important focus of research. However, to date only a few GM mouse models such as the Trp53+/−, the Tg.AC and the rasH2 models have effectively been evaluated to substitute for the two-year rodent cancer bioassays. Whether these models provide an acceptable replacement for the conventional rodent cancer bioassay for assessing human cancer risks is the subject of ongoing debate. The objective of this study was to evaluate the current status of the use of GM mice for accelerated cancer bioassays in assessing the potential human health risks associated with exposure to carcinogenic agents. We compared the published data from the GM bioassays with results obtained using the National Toxicology Program's conventional 2-year mouse cancer bioassay presently used in human cancer risk assessment. The results demonstrate a moderate success for these GM models to distinguish carcinogens from non-carcinogens. Although the GM models are less efficient in detecting rodent carcinogens, they are more consistent in identifying non-carcinogens. Our analysis also shows that there continue to be concerns about the assay design and protocols used for the GM models, including issues related to sample size, study duration, genetic instability, and reproducibility. Additional issues of concern include specific toxicity pathway-dependent effects, and differences in the potential carcinogenic mechanisms operating in GM and non-GM animals, topics that still need to be investigated. In addition, the dose-responses of the GM models can vary substantially from those seen in conventional cancer bioassays. Overall, we conclude that the existing GM mouse models are of value for hazard identification, but are of limited use for dose-response analysis with currently used study designs. Hence, until these models are thoroughly validated using more robust study designs and the dose-response issues adequately addressed, caution should be exercised when using the current GM models to assess the carcinogenic risks of chemicals to humans. Disclaimer: The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency or the National Institute of Environmental Health Sciences. Citation Format: David A. Eastmond, Suryanarayana V. Vulimiri, John E. French, Babasaheb Sonawane. An evaluation of the use of genetically modified mouse models in human cancer risk assessment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1561. doi:10.1158/1538-7445.AM2013-1561

Cadmium (Cd) exposure has been associated with increased cancer risk, and zinc (Zn) appears to reduce that risk. However, little is known about the combined influence of Cd and Zn on cancer risk. The aim of this study was to examine relationships between Cd exposure, Zn intake, and cancer mortality risks. The analyses used 5204 subjects aged 50 yr or older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) and the mortality follow-up through December 31, 2006. Cox proportional hazards models were used to test associations. In total, 569 cancer deaths were recorded during an average follow-up of 12.4 yr, including 155 from lung, 61 from prostate, and 26 from breast cancer. A positive association between Cd and cancer mortality risk was identified for both genders. Despite limited cause-specific deaths, the increased risk associated with Cd was significant for lung cancer in men. All-cause cancer mortality risk was significantly elevated among women with Zn intakes below the recommended dietary allowance (RDA) compared with women who met the RDA. The effect of low dietary Zn was not observed in men. Similar trends for prostate and breast cancer deaths were not significant. There was a significant inverse association between cancer deaths and the Zn-to-Cd ratio for both genders. Cd exposure is an important independent risk factor of cancer mortality in older Americans and the risk appears exaggerated in those with inadequate dietary Zn. Additional studies are required to elucidate the mechanism(s) by which Zn participates in the carcinogenic influence of Cd.

Exposure to xenobiotics induces complex biochemical responses in mammalian cells resulting in several perturbations in cellular toxicity pathways. Within the context of systems biology, such biochemical perturbations can be studied individually using “omics” approaches such as toxicogenomics, transcriptomics, proteomics and metabolomics (Heijne et al., 2005). The objective of this chapter is to examine how the metabolomics approach can be used in identifying the risk posed by environmental chemicals to human health using selective examples of organ toxicity. Metabolomics is a medium-to-high throughput technique employing predominantly mass spectrometry (MS) and nuclear magnetic resonance (NMR) technology (Roux et al., 2011) for the identification and characterization of endogenous metabolites of low molecular weight (<1800 Da) arising from different biochemical pathways either as primary or secondary metabolites (Idle & Gonzalez, 2007). The sum total of all small metabolites is referred to as the “metabolome”. Metabolomics has also been applied to the identification of low molecular weight, exogenous metabolites of xenobiotics (Roux et al., 2011; Rubino et al., 2009). With these capabilities, metabolomics represents a relatively quick and informative approach for assessing the physiological response to environmental chemicals.