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 s...

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Chrysotile-containing joint compound was commonly used in construction of residential and commercial buildings through the mid 1970s; however, these products have not been manufactured in the United States for more than 30 years. Little is known about actual human exposures to chrysotile fibers that may have resulted from use of chrysotile-containing joint compounds, because few exposure and no health-effects studies have been conducted specifically with these products. Because limited amounts of historical joint compounds are available (and the stability or representativeness of aged products is suspect), it is currently impossible to conduct meaningful studies to better understand the nature and magnitude of potential exposures to chrysotile that may have been associated with historical use of these products. Therefore, to support specific exposure and toxicology research activities, two types of chrysotile-containing joint compounds were produced according to original formulations from the late 1960s. To the extent possible, ingredients were the same as those used originally, with many obtained from the original suppliers. The chrysotile used historically in these products was primarily Grade 7RF9 from the Philip Carey mine. Because this mine is closed, a suitable alternate was identified by comparing the sizes and mineral composition of asbestos structures in a sample of what has been represented to be historical joint compound (all of which were chrysotile) to those in samples of three currently commercially available Grade 7 chrysotile products. The re-created materials generally conformed to original product specifications (e.g. viscosity, workability, crack resistance), indicating that these materials are sufficiently representative of the original products to support research activities.

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.

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