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Including measures of relative bioavailability (RBA) improves the accuracy of site-specific risk assessment when evaluating metals bound in matrices that resist acid digestion (alloys, slag, tailings). In vitro gastrointestinal bioaccessibility and in vivo RBA assessments were conducted using baghouse dust, surface dust, and soil collected in a neighborhood near a metal forge, which emitted metals in the form of corrosion resistant alloys. The study objective was to characterize the in vitro bioaccessibility and relative bioavailability (RBA) of cobalt and nickel when ingested as freely soluble forms (ionic salts used as the basis for oral toxicity criteria), compared to when incidentally ingested in the forms found in the environment. Test materials and standard reference materials—cobalt chloride and nickel sulfate—were administered daily for 14 or 21 days, twice daily, to juvenile swine. Daily intake doses for cobalt were ≤229 μg/kg-day, and for nickel, ≤1419 μg/kg-day. Concentrations of cobalt and nickel were measured in various tissues; 24-hour urinary excretion of each metal was also measured. Multiple linear regression modeling was performed for tissue concentration or urinary excretion vs. dose in each material, with weighting as inverse variance in each dose group. Liver, urine, and kidney provided the optimal data. Although RBA values were affected by limited absolute bioavailability of cobalt and nickel in reference materials, trends across the different biological matrices consistently showed significantly reduced bioavailability of cobalt and nickel in soil and dust, with RBAs ranging from 0.2% to 12%. Bioaccessibility of cobalt and nickel in soil and dust were 1% to 5%, and similar results were found for baghouse dust. The data demonstrate that cobalt and nickel in soil and dust affected by alloys are resistant to bioelution and absorption. This study provides useful information for site-specific risk assessments and insights for planning future research.

Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC). However, by applying a MOA analyses and human relevance framework assessment, the weight-of-evidence supports a cytotoxic MOA with the following key events: i) bolus delivery of EA to forestomach lumen and subsequent absorption, ii) cytotoxicity likely due to saturation of enzymatic detoxification, iii) chronic regenerative hyperplasia, and iv) spontaneous mutation due to increased cell replication and cell population. Clonal expansion of initiated cells thus results in late onset tumorigenesis. The key events in this 'wound and healing' MOA provide high confidence in the MOA as assessed by evolved Bradford-Hill Criteria. The weight-of-evidence supported by the proposed MOA, combined with a unique tissue that does not exist in humans, indicates that EA is highly unlikely to pose a human cancer hazard.

The determination of whether a chemical induces a specific cancer through a mutagenic or non-mutagenic mode of action (MOA) plays an important role in choosing between linear and nonlinear low-dose extrapolation to derive toxicity criteria. There is no formal framework from the U.S. EPA for determining whether environmental chemicals act through a mutagenic or non-mutagenic MOA; consequently, most such determinations are made on an ad hoc basis. Eastmond [Mutat Res 751 (2012)] recently conducted a systematic investigation of MOA determinations by U.S. and international regulatory agencies and organizations, and identified ten major factors that influence them, including toxicokinetics, in vivo genotoxicity in target organs, data quality, and evidence for alternative MOAs. We have used these ten factors to evaluate mutagenic vs. non-mutagenic MOA for gastrointestinal tumors induced by oral exposure to hexavalent chromium [Cr(VI)]. We also highlight similarities between Cr(VI) and other intestinal carcinogens previously determined to have non-genotoxic MOAs. Based on these analyses, we conclude that the MOA for Cr(VI) induced gastrointestinal tumors is non-mutagenic and that threshold risk assessment approaches are appropriate.

A cancer bioassay on hexavalent chromium Cr(VI) in drinking water reported increased incidences of duodenal tumors in B6C3F1 mice at exposures of 30-180ppm, and oral cavity tumors in F344 rats at 180ppm. A subsequent transgenic rodent (TGR) in vivo mutation assay in Big Blue® TgF344 rats found that exposure to 180ppm Cr(VI) in drinking water for 28days did not increase cII transgene mutant frequency (MF) in the oral cavity (Thompson et al., 2015). Herein, we extend our analysis to the duodenum of these same TgF344 rats. At study termination, duodenum chromium levels were below either the limit of detection or quantification in control rats, but were 24.6±3.8μg/g in Cr(VI)-treated rats. The MF in control (23.2×10-6) and Cr(VI)-treated rats (22.7×10-6) were nearly identical. In contrast, the MF in the duodenum of rats exposed to 1-ethyl-1-nitrosourea for six days (study days 1, 2, 3, 12, 19, 26) increased 24-fold to 557×10-6. These findings indicate that mutagenicity is unlikely an early initiating event in Cr(VI)-induced intestinal carcinogenesis.

Background: High incidences of breast cancer are reported in Asian women in their forties, and it is not clear whether mammographic screening for breast cancer reduces mortality among them. Nevertheless, the Korean National Cancer Screening Program (KNCSP) has implemented breast cancer screening for individuals aged 40 years and older. This study evaluated the effect of breast cancer screening in Korea. Methods: We conducted a prospective cohort of cancer-free Korean women who were invited to participate in the KNCSP between 2002 and 2003. We followed them to identify breast cancer incidence and cancer death by 2014 and 2015, respectively. Information on mammographic screening, breast cancer diagnosis, death, and causes of death was linked by identification numbers. Poisson regression was performed to estimate mortality rate ratios (MRR) for breast cancer among screened to non-screened women. Findings: A total of 8,293,240 women aged 40-79 years were included in the analysis. Breast cancer incidence rates were 84.41 and 82.88 per 100,000 women-years for screened and non-screened women, respectively, with an adjusted rate ratio of 1.09 (95% CI, 1.08-1.11). Breast cancer mortality rates were 5.81 and 13.43 per 100,000 women-years for screened and non-screened women, respectively, with an adjusted MRR of 0.43 (95% CI, 0.41-0.44). The greatest mortality reduction was noted among women aged 45 to 54 years, and there was no observable reduction in mortality after the age of 70 years. Interpretations: The KNCSP for breast cancer has been effective in reducing breast cancer mortality for Korean women aged 40-69 years, doing so by 22%. Funding Statement: This study was supported by a Grant-in-Aid for Cancer Research and Control from the National Cancer Center of Korea (1910231-1). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Institutional Review Board of the National Cancer Center, Korea (Institutional Review Board no. NCCNCS08129).

Objectives We aimed to evaluate the distribution, clinical presentations and severity of common acute respiratory infections (ARI) viruses in infants across 3 clinical settings. Study design In a prospective virus surveillance study, infants under 1 year with fever and/or respiratory symptoms were enrolled from outpatient, emergency department, and inpatient settings from December 16, 2019 through April 30, 2020. Demographic and clinical characteristics were collected through parent/guardian interviews, medical chart abstractions, and follow-up surveys. Nasal swabs were collected and tested for viruses using quantitative reverse-transcription polymerase chain reaction. Results We enrolled 366 infants and tested nasal swabs on 360 (98%); median age was 6.3 months, 50% male. In total, 295 (82%) had at least 1 virus detected; rhinovirus/enterovirus (RV/EV; 42%), respiratory syncytial virus (RSV; 34%), and influenza (15%) were the most common. RSV was the most frequently detected virus in the inpatient (63%) and emergency department (37%) settings, and RV/EV was most frequently detected virus in the outpatient setting (54%). RSV-positive infants had a lower median age (4.9 months) and were more likely to have respiratory distress, and RV/EV-positive infants were less likely to have respiratory distress. Influenza-positive infants had a higher median age (8 months) and were more likely to have systemic symptoms. RSV infection and younger age were associated with higher odds of hospitalization in multivariable logistic regression. Conclusions Across 3 clinical settings, and combining virologic, patient, and health-system information, our results highlight the burden of viral ARI among infants. Overall, RSV, RV/EV, and influenza were most commonly detected, with RSV having the highest disease severity.

Titanium dioxide (TiO2) has been characterized as a poorly soluble particulate (PSP) with low toxicity. It is well accepted that low toxicity PSPs such as TiO2 induce lung tumors in rats when deposition overwhelms particle clearance mechanisms. Despite the sensitivity of rats to PSPs and questionable relevance of PSP-induced tumors to humans, TiO2 is listed as a possible human carcinogen by some agencies and regulators. Thus, environmental toxicity criteria for TiO2 are needed for stakeholders to evaluate potential risks from environmental exposure and regulatory compliance. A systematic review of the literature was conducted to characterize the available data and identify candidate datasets upon which toxicity values could be derived. Key to this assessment, a survey of mechanistic data relevant for lung cancer was used to support quantitative inhalation risk assessment approaches. A total of 473 human studies were identified, 7 of which were epidemiological studies that met inclusion criteria to quantitatively characterize carcinogenic endpoints in humans. None of these studies supported derivation of toxicity criteria; therefore, animal data were used to derived safety values for TiO2 using different dose-metrics (regional deposited dose ratios, TiO2 particle surface area lung burden, and volumetric overload of alveolar macrophages), benchmark dose modeling, and different low-dose extrapolation approaches. Based on empirical evidence and mechanistic support for nonlinear mode of action involving particle overload, chronic inflammation and cell proliferation, a no significant risk level (NSRL) of 300 μg/day was derived. By comparison, low-dose linear extrapolation from tumor incidence in the rat lung resulted in an NSRL value of 44 μg/day. These toxicity values should be useful for stakeholders interested in assessing risks from environmental exposure to respirable TiO2.

Cobalt compounds (metal, salts, hard metals, oxides, and alloys) are used widely in various industrial, medical and military applications. Chronic inhalation exposure to cobalt metal and cobalt sulfate has caused lung cancer in rats and mice, as well as systemic tumors in rats. Cobalt compounds are listed as probable or possible human carcinogens by some agencies, and there is a need for quantitative cancer toxicity criteria. The U.S. Environmental Protection Agency has derived a provisional inhalation unit risk (IUR) of 0.009 per μg/m3 based on a chronic inhalation study of soluble cobalt sulfate heptahydrate; however, a recent 2-year cancer bioassay affords the opportunity to derive IURs specifically for cobalt metal. The mechanistic data support that the carcinogenic mode of action (MOA) is likely to involve oxidative stress, and thus, non-linear/threshold mechanisms. However, the lack of a detailed MOA and use of high, toxic exposure concentrations in the bioassay (≥1.25 mg/m3) preclude derivation of a reference concentration (RfC) protective of cancer. Several analyses resulted in an IUR of 0.003 per μg/m3 for cobalt metal, which is ∼3-fold less potent than the provisional IUR. Future research should focus on establishing the exposure-response for key precursor events to improve cobalt metal risk assessment.

Recent analyses-highlighted by the International Workshops on Genotoxicity Testing Working Group on Quantitative Approaches to Genetic Toxicology Risk Assessment-have identified a correlation between (log) estimates of a carcinogen's in vivo genotoxic potency and in vivo carcinogenic potency in typical laboratory animal models, even when the underlying data have not been matched for tissue, species, or strain. Such a correlation could have important implications for risk assessment, including informing the mode of action (MOA) of specific carcinogens. When in vivo genotoxic potency is weak relative to carcinogenic potency, MOAs other than genotoxicity (e.g., endocrine disruption or regenerative hyperplasia) may be operational. Herein, we review recent in vivo genotoxicity and carcinogenicity data for hexavalent chromium (Cr(VI)), following oral ingestion, in relevant tissues and species in the context of the aforementioned correlation. Potency estimates were generated using benchmark doses, or no-observable-adverse-effect-levels when data were not amenable to dose-response modeling. While the ratio between log values for carcinogenic and genotoxic potency was ≥1 for many compounds, the ratios for several Cr(VI) datasets (including in target tissue) were less than unity. In fact, the ratios for Cr(VI) clustered closely with ratios for chloroform and diethanolamine, two chemicals posited to have non-genotoxic MOAs. These findings suggest that genotoxicity may not play a major role in the cancers observed in rodents following exposure to high concentrations of Cr(VI) in drinking water-a finding consistent with recent MOA and adverse outcome pathway (AOP) analyses concerning Cr(VI). This semi-quantitative analysis, therefore, may be useful to augment traditional MOA and AOP analyses. More case examples will be needed to further explore the general applicability and validity of this approach for human health risk assessment.

Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m(3)), for which clear exposure-response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose-response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation of particulate chromium in the bifurcations of the lung resulting in exceedance of clearance mechanisms and cellular absorption of Cr(VI). Once inside the cell, reduction of Cr(VI) results in oxidative stress and the formation of Cr ligands. Subsequent protein and DNA damage lead to tissue irritation, inflammation, and cytotoxicity. These effects, concomitant with increased cell proliferation, result in changes to DNA sequences and/or methylation status that can lead to tumorigenesis. This MOA supports the use of non-linear approaches when extrapolating lung cancer risk occurring at high concentration occupational exposures to environmentally-relevant exposures.

Hexavalent chromium [Cr(VI)] induces hematological signs of microcytic anemia in rodents. Considering that Cr(VI) can oxidize ferrous (Fe(2+)) to ferric (Fe(3+)) iron, and that only the former is transported across the duodenum, we hypothesize that, at high concentrations, Cr(VI) oxidizes Fe(2+) in the lumen of the small intestine and perturbs iron absorption. Herein we report that 90-day exposure to Cr(VI) in drinking water resulted in dose-dependent decreases in Fe levels in the duodenum, liver, serum, and bone marrow. Toxicogenomic analyses from the duodenum indicate responses consistent with Fe deficiency, including significant induction of divalent metal transporter 1 (DMT1, Slc11a2) and transferrin receptor 1 (TFR1, Tfr1). In addition, at ⩾20mg Cr(VI)/L in drinking water, Cr RBC:plasma ratios in rats were increased and exceeded unity, indicating saturation of reductive capacity and intracellular absorption of Cr(VI) into red blood cells (RBCs). These effects occurred in both species but were generally more severe in rats. These data suggest that high concentrations of Cr(VI) in drinking limit Fe absorption and alter iron homeostasis. Furthermore, some effects observed at high doses in recent Cr(VI) chronic and subchronic bioassays may be explained, at least in part, by iron deficiency and disruption of homeostasis.

Background There is currently insufficient evidence to confirm the effect of ambient air pollution on mental disorders, especially among susceptible populations. This study investigated the short-term effect of ambient air pollution on the risk of depressive episode and the effect modification across disease subpopulations. Methods Subjects who visited the emergency department (ED) for depressive episode from 2005 to 2009 ( n =4985) in Seoul, Republic of Korea were identified from medical claims data. We conducted a time-stratified case-crossover study using conditional logistic regression. Subgroup analyses were conducted after the subjects were stratified by underlying disease (cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, asthma, and depressive disorder). The risk was expressed as an odds ratio (OR) per 1 standard deviation of each air pollutant. Results SO 2 , PM 10 , NO 2 , and CO were positively associated with ED visits for depressive episode. The maximum risk was observed in the distributed lag 0–3 model for PM 10 (OR, 1.120; 95% confidence interval, 1.067–1.176). PM 10 , NO 2 , and CO significantly increased the risks of ED visits for depressive episode in subjects with either underlying cardiovascular disease, diabetes mellitus, asthma, or depressive disorder. Limitations Our data may include a misclassification bias due to the validity of a diagnosis determined from medical services utilization data. Conclusions SO 2 , PM 10 , NO 2 , and CO significantly increased the risk of ED visits for depressive episode, especially among individuals with pre-existing cardiovascular disease, diabetes mellitus, or asthma.

A previously published human PBPK model for manganese (Mn) in infants and children has been updated with Mn in drinking water as an additional exposure source. Built upon the ability to capture differences in Mn source-specific regulation of intestinal uptake in nursing infants who are breast-fed and formula-fed, the updated model now describes the bioavailability of Mn from drinking water in children of ages 0-18. The age-related features, including the recommended age-specific Mn dietary intake, age-specific water consumption rates, and age-specific homeostasis of Mn, are based on the available human data and knowledge of the biology of essential-metal homeostasis. Model simulations suggest that the impact of adding drinking-water exposure to daily Mn exposure via dietary intake and ambient air inhalation in children is not greater than the impacts in adults, even at a drinking-water concentration that is 2 times higher than the USEPA's lifetime health advisory value. This conclusion was also valid for formula-fed infants who are considered at the highest potential exposure to Mn from drinking water compared to all other age groups. Our multi-route, multi-source Mn PBPK model for infants and children provides insights about the potential for Mn-related health effects on growing children and will thereby improve the level of confidence in properly interpreting Mn exposure-health effects relationships in children in human epidemiological studies.

In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia – suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI)-induced intestinal carcinogenesis. Limitations to this analysis will also be discussed.

Background & Aims It is not clear whether screening for gastric cancer by upper endoscopy or upper gastrointestinal (UGI) series examinations (looking at the upper and middle sections of the gastrointestinal tract by imaging techniques) reduces mortality. Nevertheless, the Korean National Cancer Screening Program for gastric cancer was launched in 1999 to screen individuals 40 years and older for gastric cancer using these techniques. We evaluated the effectiveness of these techniques in gastric cancer detection and compared their effects on mortality in the Korean population. Methods We performed a nested case−control study using data from the Korean National Cancer Screening Program for gastric cancer since 2002. A total of 16,584,283 Korean men and women, aged 40 years and older, comprised the cancer-free cohort. Case subjects (n = 54,418) were defined as individuals newly diagnosed with gastric cancer from January 2004 through December 2009 and who died before December 2012. Cases were matched with controls (subjects who were alive on the date of death of the corresponding case subject, n = 217,672) for year of entry into the study cohort, age, sex, and socioeconomic status. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained via conditional logistic regression analysis. Results Compared with subjects who had never been screened, the overall OR for dying from gastric cancer among ever-screened subjects was 0.79 (95% CI, 0.77–0.81). According to screening modality, the ORs of death from gastric cancer were 0.53 (95% CI, 0.51–0.56) for upper endoscopy and 0.98 (95% CI, 0.95–1.01) for UGI series. As the number of endoscopic screening tests performed per subject increased, the ORs of death from gastric cancer decreased: 0.60 (95% CI, 0.57–0.63), 0.32 (95% CI, 0.28–0.37), and 0.19 (95% CI, 0.14–0.26) for once, twice, and 3 or more times, respectively. Conclusions Within the Korean National Cancer Screening Program, patients who received an upper endoscopy were less likely to die from gastric cancer; no associations were found for UGI series.