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.

A Risk-Based Strategy for Evaluating Mitigation Options for Process-Formed Compounds in Food: Workshop Proceedings.

Processing (eg, cooking, grinding, drying) has changed the composition of food throughout the course of human history; however, awareness of process-formed compounds, and the potential need to mitigate exposure to those compounds, is a relatively recent phenomenon. In May 2015, the North American Branch of the International Life Sciences Institute (ILSI North America) Technical Committee on Food and Chemical Safety held a workshop on the risk-based process for mitigation of process-formed compounds. This workshop aimed to gain alignment from academia, government, and industry on a risk-based process for proactively assessing the need for and benefit of mitigation of process-formed compounds, including criteria to objectively assess the impact of mitigation as well as research needed to support this process. Workshop participants provided real-time feedback on a draft framework in the form of a decision tree developed by the ILSI North America Technical Committee on Food and Chemical Safety to a panel of experts, and they discussed the importance of communicating the value of such a process to the larger scientific community and, ultimately, the public. The outcome of the workshop was a decision tree that can be used by the scientific community and could form the basis of a global approach to assessing the risks associated with mitigation of process-formed compounds.

Assessment of the in vivo genotoxic potential of three smoke flavoring primary product mixtures.

Smoke flavorings are mixtures generated from wood pyrolysis that are filtered to remove tar and are often considered healthier alternatives to conventional smoking processes. While the latter is mostly unregulated, smoke-flavoring primary products (SFPPs) are undergoing the 10-year required re-evaluation in the European Union (EU). To comply with recent smoke flavor guidance, in vivo micronucleus studies in rats and transgenic rodent (TGR) mutation assays in Muta™Mice were conducted on three SFPPs. For most studies, typical limit doses were exceeded to comply with regulatory requests. Exposure to SFPPs by oral gavage did not result in significant increases in bone marrow micronucleus formation. Except for one group, exposure to SFPPs via feed for 28 days did not result in significant increases in mutant frequency (MF) in the glandular stomach or liver. One group exposed to a maximal feasible dietary dose of 50,000 ppm (>10,000 mg/kg bodyweight per day) exhibited a statistically significant increase in liver MF; however, the MF in all mice in this group were within the historical vehicle control 95% quantile confidence intervals and therefore not considered biologically relevant. Based on estimates of human dietary exposure to each SFPP, the margin of exposure (MOE) values in the TGR assays exceed 10,000. The MOE for one unintentionally present constituent, 2,5(H)-furanone, also exceeds 10,000. Collectively, these data indicate that these SFPPs pose no genotoxic risk and are safe alternatives to conventional smoking.

More on the dynamics of dust generation: the effects of mixing and sanding chrysotile, calcium carbonate, and other components on the characteristics of joint-compound dusts.

An ongoing research effort designed to reconstruct the character of historical exposures associated with use of chrysotile-containing joint compounds naturally raised questions concerning how the character (e.g. particle size distributions) of dusts generated from use of recreated materials compares to dusts from similar materials manufactured historically. This also provided an opportunity to further explore the relative degree that the characteristics of dusts generated from a bulk material are mediated by the properties of the bulk material versus the mechanical processes applied to the bulk material by which the dust is generated. In the current study, the characteristics of dusts generated from a recreated ready mix and recreated dry mix were compared to each other, to dusts from a historical dry mix, and to dusts from the commercial chrysotile fiber (JM 7RF3) used in the recreated materials. The effect of sanding on the character of dusts generated from these materials was also explored. Dusts from the dry materials studied were generated and captured for analysis in a dust generator-elutriator. The recreated and historical joint compounds were also prepared, applied to drywall, and sanded inside sealed bags so that the particles produced from sanding could be introduced into the elutriator and captured for analysis. Comparisons of fiber size distributions in dusts from these materials suggest that dust from commercial fiber is different from dusts generated from the joint compounds, which are mixtures, and the differences persist whether the materials are sanded or not. Differences were also observed between sanded recreated ready mix and either the recreated dry mix or a historical dry mix, again whether sanded or not. In all cases, however, such differences disappeared when variances obtained from surrogate data were used to better represent the 'irreducible variation' of these materials. Even using the smaller study-specific variances, no differences were observed between the recreated dry mix and the historical dry mix, indicating that chrysotile-containing joint compounds can be recreated using historical formulations such that the characteristics of the modern material reasonably mimic those of a corresponding historical material. Similarly, no significant differences were observed between dusts from sanded and unsanded versions of similar materials, suggesting (as in previous studies) that the characteristics of asbestos-containing dusts are mediated primarily by the properties of the bulk material from which they are derived.

Chamber for testing asbestos-containing products: validation and testing of a re-created chrysotile-containing joint compound.

Joint compound products containing chrysotile asbestos were commonly used for building construction from the late 1940s through the mid-1970s. Few relevant data exist to support reconstructing historical worker exposures to fibers generated by working with this material. Therefore, we re-created 1960s-era chrysotile-containing joint compound (JCC) and compared its characteristics to a current-day asbestos-free joint compound (JCN). Validation studies showed that a bench-scale chamber with controlled flow dynamics, designed to quantify particulate emissions from joint compound products, provided precise and reliable measurements of generated airborne dust mass, chrysotile fiber concentrations, and corresponding activity-specific emission rates. Subsequent chamber studies characterized fibers counted by phase contrast microscopy (PCM) per mass of respirable dusts and total suspended particulate dusts (total dusts), generated during JCC sanding or sweeping, as well as corresponding dust emission rates for JCC and JCN, and the ratio of total to respirable dust mass for JCN. From these data we estimated factors, F(CH-rd) and F(CH-td) (in units of f cm(-3) per mg m(-3)), by which respirable JCN dust mass concentrations collected during construction use can be converted to corresponding airborne PCM fiber concentrations generated by sanding or sweeping JCC. For sanding, median values (95% confidence limits) of F(CH-rd) and F(CH-td) were estimated to be 0.044 (0.039-0.050) and 0.212 (0.115-0.390) f cm(-3) per mg m(-3), respectively. The F(CH-td) to F(CH-rd) ratio indicates that approximately five times as many airborne PCM fibers are anticipated per unit air volume sampled when JCC dust is collected on cassettes (as done historically), than when respirable JCC dust is collected on cyclones. As the sizes of individual fibers collected appear to be primarily respirable, this difference may be a sampling artifact and suggests caution in interpreting historical fiber concentration measures made using cassettes during work with JCC-like materials. F(CH-rd) can be used with published and newly generated field measurements of respirable dust mass concentrations associated with the use of JCN or equivalent JCN materials to better characterize historical worker exposures to PCM fibers from use of JCC or equivalent JCCs. The experimental process described also can be used to develop conversion factors for other combinations of modern-day asbestos-free and historical chrysotile-containing products.

Development of updated RfD and RfC values for medium carbon range aromatic and aliphatic total petroleum hydrocarbon fractions.

Using total petroleum hydrocarbon (TPH) measurements as a tool for assessing potential human health risks associated with exposures to petroleum products in the environment poses unique challenges, as TPH represents highly variable and complex mixtures containing hundreds of individual chemicals with wide-ranging chemical and physical properties. Current risk assessment practice generally involves analysis of environmental samples for various TPH fractions and summation of risk across those fractions. The United States Environmental Protection Agency (USEPA) derived provisional toxicity criteria for low, medium, and high carbon range aromatic and aliphatic hydrocarbon fractions over a decade ago. These criteria have been used, in whole or in part, to derive risk-based cleanup levels for TPH contamination in soil and groundwater. Herein, we evaluate and update oral and inhalation toxicity criteria for two of these fractions - medium carbon range aromatics and aliphatics - using, where applicable, newer data, updated modeling techniques, and new/alternative analyses of certain endpoints, human relevance, and uncertainty. The results of the analyses support an ~10-fold increase in the USEPA provisional reference concentration (p-RfC) values from 0.1 mg/m3 to 1 mg/m3 for both medium carbon range aromatics (different uncertainty factor) and aliphatics (new study and different judgment of toxicity data from existing study). Compared to the USEPA provisional oral reference dose (p-RfD) values for the medium carbon range aromatics and aliphatics of 0.03 mg/kg-day and 0.01 mg/kg-day, respectively, the present analyses suggest the RfD for medium carbon range aromatics could be increased >6.6-fold to 0.2 mg/kg-day (updated modeling and different uncertainty factors), and the RfD for medium carbon range aliphatics could be increased ~20-fold to 0.2 mg/kg-day (new study). These updated toxicity criteria could be used by regulatory agencies to reevaluate risk-based screening levels or by risk managers to support cleanup levels for medium carbon range aromatics and aliphatics, while still ensuring adequate health protection.Implications: Petroleum products represent complex mixtures of hydrocarbons broadly comprised of aliphatic compounds (straight-chain, branched-chain, and cyclic alkanes and alkenes) and aromatic compounds such as benzene, alkylbenzenes, and polycyclic aromatic hydrocarbons. The complex nature of petroleum products presents challenges for assessing potential health risks associated with exposure to petroleum hydrocarbon contamination in the environment. It has been over ten years since the U.S. Environmental Protection Agency derived provisional toxicity criteria for low, medium, and high carbon range aromatic and aliphatic hydrocarbon fractions. In that time, risk assessment guidance and tools have evolved, and new studies have been published. Our analyses indicate that current provisional toxicity criteria for medium carbon range aromatics and aliphatics fractions are overly conservative by approximately an order of magnitude.

Benzene inhalation by parts washers: new estimates based on measures of occupational exposure to solvent coaromatics.

Questions persist regarding assessment of workers' exposures to products containing low levels of benzene, such as mineral spirit solvent (MSS). This study summarizes previously unpublished data for parts-washing activities, and evaluates potential daily and lifetime cumulative benzene exposures incurred by workers who used historical and current formulations of a recycled mineral spirits solvent in manual parts washers. Measured benzene concentrations in historical samples from parts-washing operations were frequently below analytical detection limits. To better assess benzene exposure among these workers, air-to-solvent concentration ratios measured for toluene, ethylbenzene, and xylenes (TEX) were used to predict those for benzene based on a statistical model, conditional on physical-chemical theory supported by new thermodynamic calculations of TEX and benzene activity coefficients in a modeled MSS-type solvent. Using probabilistic methods, the distributions of benzene concentrations were then combined with distributions of other exposure parameters to estimate eight-hour time-weighted average (TWA) exposure concentration distributions and corresponding daily respiratory dose distributions for workers using these solvents in parts washers. The estimated 50th (95th) percentile of the daily respiratory dose and corresponding eight-hour TWA air concentration for workers performing parts washing are 0.079 (0.77) mg and 0.0030 (0.028) parts per million by volume (ppm) for historical solvent, and 0.020 (0.20) mg and 0.00078 (0.0075) ppm for current solvent, respectively. Both 95th percentile eight-hour TWA respiratory exposure estimates for solvent formulations are less than 10% of the current Occupational Safety and Health Administration permissible exposure limit of 1.0 ppm for benzene.

Evaluation of potential human health risk associated with consumption of edible products from livestock fed ration supplemented with Red Lake Diatomaceous Earth.

Red Lake Diatomaceous Earth (DE) is a naturally occurring blend of diatomaceous earth and calcium bentonite that can be used as an anti-caking agent in animal feed and contains naturally occurring dioxins. A quantitative risk assessment was conducted to assess potential human health risk associated with consumption of edible tissues from livestock exposed to dioxins via feed containing Red Lake DE. Empirical data characterising the transfer of dioxins to eggs and other tissues in chickens demonstrate that resulting concentrations in eggs are lower than those found in the general food supply. These data also provided product-specific input for a risk assessment conducted both with default parameters and with media-specific input from the feed study. Results demonstrate that exposure to dioxins in edible tissue from livestock that consumed Red Lake DE in feed would not be associated with an increased risk to humans. Findings from this assessment highlight the utility and importance of accounting for bioavailability as part of health-based risk assessment and provide information critical to risk managers in determining the safe use of Red Lake DE as an anticaking agent in livestock and pet feed.

Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children.

To date, one of the most heavily cited assessments of caffeine safety in the peer-reviewed literature is that issued by Health Canada (Nawrot et al., 2003). Since then, >10,000 papers have been published related to caffeine, including hundreds of reviews on specific human health effects; however, to date, none have compared the wide range of topics evaluated by Nawrot et al. (2003). Thus, as an update to this foundational publication, we conducted a systematic review of data on potential adverse effects of caffeine published from 2001 to June 2015. Subject matter experts and research team participants developed five PECO (population, exposure, comparator, and outcome) questions to address five types of outcomes (acute toxicity, cardiovascular toxicity, bone and calcium effects, behavior, and development and reproduction) in four healthy populations (adults, pregnant women, adolescents, and children) relative to caffeine intake doses determined not to be associated with adverse effects by Health Canada (comparators: 400 mg/day for adults [10 g for lethality], 300 mg/day for pregnant women, and 2.5 mg/kg/day for children and adolescents). The a priori search strategy identified >5000 articles that were screened, with 381 meeting inclusion/exclusion criteria for the five outcomes (pharmacokinetics was addressed contextually, adding 46 more studies). Data were extracted by the research team and rated for risk of bias and indirectness (internal and external validity). Selected no- and low-effect intakes were assessed relative to the population-specific comparator. Conclusions were drawn for the body of evidence for each outcome, as well as endpoints within an outcome, using a weight of evidence approach. When the total body of evidence was evaluated and when study quality, consistency, level of adversity, and magnitude of response were considered, the evidence generally supports that consumption of up to 400 mg caffeine/day in healthy adults is not associated with overt, adverse cardiovascular effects, behavioral effects, reproductive and developmental effects, acute effects, or bone status. Evidence also supports consumption of up to 300 mg caffeine/day in healthy pregnant women as an intake that is generally not associated with adverse reproductive and developmental effects. Limited data were identified for child and adolescent populations; the available evidence suggests that 2.5 mg caffeine/kg body weight/day remains an appropriate recommendation. The results of this systematic review support a shift in caffeine research to focus on characterizing effects in sensitive populations and establishing better quantitative characterization of interindividual variability (e.g., epigenetic trends), subpopulations (e.g., unhealthy populations, individuals with preexisting conditions), conditions (e.g., coexposures), and outcomes (e.g., exacerbation of risk-taking behavior) that could render individuals to be at greater risk relative to healthy adults and healthy pregnant women. This review, being one of the first to apply systematic review methodologies to toxicological assessments, also highlights the need for refined guidance and frameworks unique to the conduct of systematic review in this field.

A 3-week dietary safety study of octenyl succinic anhydride (OSA)-modified starch in neonatal farm piglets.

Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2 days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20 g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20 g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth.

Re: Evaluation of the size and type of free particulates collected from unused asbestos-containing brake components as related to potential for respirability.

BACKGROUND: In Atkinson et al. 2004 rinsates of unused brake components were analyzed by transmission electron microscopy (TEM) for the presence of asbestos fibers. RESULTS: We do not believe that the findings of Atkinson et al. are informative and could have been predicted based on the study design and the fact that one would expect to find measurable TEM asbestos fibers on an unused brake component. We also find that the paper did not provide a full or even partial discussion of the published literature with respect to industrial hygiene or epidemiology data. CONCLUSION: The findings of Atkinson et al. do not, in our view, "further raise concerns" about historical asbestos exposures experienced by automotive mechanics because of the vast amount of published literature to the contrary.

Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a "state-of-the-art" review.

Throughout the history of automobile development, chrysotile asbestos has been an essential component of vehicle brake linings and pads. Acceptable alternatives were not fully developed until the 1980s, and these were installed in vehicles produced over the past decade. This article presents a "state-of-the-art" analysis of what was known over time about the potential environmental and occupational health hazards associated with the presence of chrysotile asbestos in brake linings and pads. As part of this analysis, the evolution of automobile brakes and brake friction materials, beginning with the early 1900s, is described. Initial concerns regarding exposures to asbestos among workers involved in the manufacture of friction products were raised as early as 1930. Between 1930 and 1959, eight studies were conducted for which friction product manufacturing workers were part of the population assessed. These studies provided evidence of asbestosis among highly exposed workers, but provided little information on the magnitude of exposure. The U.S. Public Health Service proposed the first occupational guideline for asbestos exposure in 1938. The causal relationship between asbestos exposure and lung cancer was confirmed in 1955 in asbestos textile workers in the United Kingdom, and later, in 1960, in South Africa, mesothelioma was attributed to asbestos exposure to even relatively low airborne concentrations of crocidolite. Between 1960 and 1974, five epidemiology studies of friction product manufacturing workers were conducted. During this same time period, the initial studies of brake lining wear (dust or debris) emissions were conducted showing that automobile braking was not a substantial contributor of asbestos fibers greater than 5 microm in length to ambient air. The first exposure surveys, as well as preliminary health effects studies, for brake mechanics were also conducted during this period. In 1971, the Occupational Safety and Health Administration promulgated the first national standards for workplace exposure to asbestos. During the post-1974 time period, most of the information on exposure of brake mechanics to airborne asbestos during brake repair was gathered, primarily from a series of sampling surveys conducted by the National Institute of Occupational Safety and Health in the United States. These surveys indicated that the time-weighted average asbestos