Probabilistic risk assessment of residential exposure to electric arc furnace steel slag using Bayesian model of relative bioavailability and PBPK modeling of manganese.

Electric arc furnace (EAF) slag is a coproduct of steel production used primarily for construction purposes. Some applications of EAF slag result in residential exposures by incidental ingestion and inhalation of airborne dust. To evaluate potential health risks, an EAF slag characterization program was conducted to measure concentrations of metals and leaching potential (including oral bioaccessibility) in 38 EAF slag samples. Arsenic, hexavalent chromium, iron, vanadium, and manganese (Mn) were identified as constituents of interest (COIs). Using a probabilistic risk assessment (PRA) approach, estimated distributions of dose for COIs were assessed, and increased cancer risks and noncancer hazard quotients (HQs) at the 50th and 95th percentiles were calculated. For the residents near slag-covered roads, cancer risk and noncancer HQs were <1E - 6 and 1, respectively. For residential driveway or landscape exposure, at the 95th percentile, cancer risks were 1E - 6 and 7E - 07 based on oral exposure to arsenic and hexavalent chromium, respectively. HQs ranged from 0.07 to 2 with the upper bound due to ingestion of Mn among children. To expand the analysis, a previously published physiologically based pharmacokinetic (PBPK) model was used to estimate Mn levels in the globus pallidus for both exposure scenarios and further evaluate the potential for Mn neurotoxicity. The PBPK model estimated slightly increased Mn in the globus pallidus at the 95th percentile of exposure, but concentrations did not exceed no-observed-adverse-effect levels for neurological effects. Overall, the assessment found that the application of EAF slag in residential areas is unlikely to pose a health hazard or increased cancer risk.

Industry-wide review of potential worker exposure to 1,3-butadiene during chemical manufacturing and processing as a reactant.

Among the first 20 high-priority chemical substances selected by USEPA to undergo risk evaluation as part of the Toxic Substances Control Act, as amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act of 2016 is 1,3-butadiene (1,3-BD). Because much of the literature related to occupational exposure to 1,3-BD is associated with the use of the substance in synthetic rubber production and few data have been published for exposures to 1,3-BD manufacturing workers, existing industrial hygiene data collected at facilities where the substance is manufactured or processed as a reactant were compiled and analyzed. The dataset was comprised of personal air samples collected between 2010 and 2019 at facilities located throughout the United States and was compiled into a single database using a uniform data collection template. Data designated by the companies as full-shift were stratified by job group and one of three operational conditions of the workplace: routine, turnaround, and non-routine. Data designated by the companies as short-term and task-level were stratified by task description, sample duration, and operational condition. The final aggregated database contained a total of 5,676 full-shift personal samples. Mean concentrations of 1,3-BD for the job groups ranged from 0.012 ppm to 0.16 ppm. High-end estimates of 1,3-BD air concentrations for the job groups under routine operations ranged from 0.014 ppm to 0.23 ppm. The aggregated database also included 1,063 short-term and task-level personal samples. For short-term samples (< =15 min), mean concentrations ranged from 0.49 ppm to 3.9 ppm, with the highest concentrations observed for the cleaning and maintaining equipment tasks. For task samples with durations greater than 15 min, mean concentrations ranged from 0.49 to 3.6 ppm, with the highest concentrations observed for the unloading and loading task. In addition to the personal air sampling records, information on the use of PPE during various tasks was compiled and analyzed. This data set provides robust quantitative air concentration data and exposure control information for which occupational exposures to 1,3-BD in the Manufacturing and Processing as a Reactant condition of use can be assessed.

Hexavalent chromium and stomach cancer: a systematic review and meta-analysis.

Hexavalent chromium [Cr(VI)] is known to cause lung cancer in workers of certain industries, but an association with stomach cancer is uncertain and widely debated. Systematic review and meta-analyses were conducted to assess the risk of stomach cancer mortality/morbidity in humans and experimental animals exposed to Cr(VI). In accordance with the protocol (PROSPERO #CRD4201605162), searches in PubMed and Embase®, and reviews of secondary literature bibliographies, were used to identify eligible studies. Critical appraisal of internal validity and qualitative integration were carried out using the National Toxicology Program's Office of Health Assessment and Translation (OHAT) approach; meta-analyses were conducted based on the occupational data (the only data suitable for quantitative assessment). Forty-seven publications (3 animal, 44 occupational, 0 non-occupational) met the eligibility criteria. Stomach cancer was only observed in one high risk of bias animal study, and in the low risk of bias studies no stomach cancer was observed. Thus, confidence in this evidence base is high. Environmental epidemiology studies did not meet eligibility criteria because exposure and outcome were not measured at the individual level. Meta-analyses of human data resulted in overall meta relative risks of 1.08 (95% CI: 0.96-1.21) including all studies and 1.03 (95%CI: 0.84-1.26) excluding studies associated with the highest risk of bias. Because most occupational studies have high risk of bias for confounding and exposure domains, the overall confidence in this evidence base is low to moderate. Combining the streams of evidence per the OHAT approach, Cr(VI) does not pose a stomach cancer hazard in humans.

Inhalation cancer risk assessment of cobalt metal.

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/m(3) 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/m(3)) preclude derivation of a reference concentration (RfC) protective of cancer. Several analyses resulted in an IUR of 0.003 per µg/m(3) 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.

Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations.

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.

Inhalation cancer risk assessment of hexavalent chromium based on updated mortality for Painesville chromate production workers.

The exposure-response for hexavalent chromium (Cr(VI))-induced lung cancer among workers of the Painesville Ohio chromate production facility has been used internationally for quantitative risk assessment of environmental and occupational exposures to airborne Cr(VI). We updated the mortality of 714 Painesville workers (including 198 short-term workers) through December 2011, reconstructed exposures, and conducted exposure-response modeling using Poisson and Cox regressions to provide quantitative lung cancer risk estimates. The average length of follow-up was 34.4 years with 24,535 person-years at risk. Lung cancer was significantly increased for the cohort (standardized mortality ratio (SMR)=186; 95% confidence interval (CI) 145-228), for those hired before 1959, those with >30-year tenure, and those with cumulative exposure >1.41 mg/m(3)-years or highest monthly exposures >0.26 mg/m(3). Of the models assessed, the linear Cox model with unlagged cumulative exposure provided the best fit and was preferred. Smoking and age at hire were also significant predictors of lung cancer mortality. Adjusting for these variables, the occupational unit risk was 0.00166 (95% CI 0.000713-0.00349), and the environmental unit risk was 0.00832 (95% CI 0.00359-0.0174), which are 20% and 15% lower, respectively, than values developed in a previous study of this cohort.

Synchrotron-based imaging of chromium and γ-H2AX immunostaining in the duodenum following repeated exposure to Cr(VI) in drinking water.

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodena from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum--the latter evidenced by lengthening of the crypt compartment by ∼2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. These findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia.