A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire.

Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.

Rethinking Meta-Analysis: Applications for Air Pollution Data and Beyond.

Meta-analyses offer a rigorous and transparent systematic framework for synthesizing data that can be used for a wide range of research areas, study designs, and data types. Both the outcome of meta-analyses and the meta-analysis process itself can yield useful insights for answering scientific questions and making policy decisions. Development of the National Ambient Air Quality Standards illustrates many potential applications of meta-analysis. These applications demonstrate the strengths and limitations of meta-analysis, issues that arise in various data realms, how meta-analysis design choices can influence interpretation of results, and how meta-analysis can be used to address bias and heterogeneity. Reviewing available data from a meta-analysis perspective can provide a useful framework and impetus for identifying and refining strategies for future research. Moreover, increased pervasiveness of a meta-analysis mindset-focusing on how the pieces of the research puzzle fit together-would benefit scientific research and data syntheses regardless of whether or not a quantitative meta-analysis is undertaken. While an individual meta-analysis can only synthesize studies addressing the same research question, the results of separate meta-analyses can be combined to address a question encompassing multiple data types. This observation applies to any scientific or policy area where information from a variety of disciplines must be considered to address a broader research question.

Review of animal studies on the cardiovascular effects of caffeine.

To address the safety of caffeine levels in energy drinks, we previously conducted a detailed evaluation of epidemiology studies in humans consuming coffee/caffeine, in which we assessed multiple health effects (unpublished). To further evaluate the effects of caffeine on the cardiovascular system, we turned to animal studies, which often use pure caffeine (not coffee), frequently at higher doses than those typical of human exposure. We identified key scientific studies and reviews in which effects of coffee or caffeine were evaluated in animals by conducting a comprehensive PubMed literature search and analyzing the results. We found that the human equivalent dose (HED) for the no observed adverse effect level (NOAEL) for cardiovascular effects was 260 mg caffeine (2-3 cups of coffee) for a single dose of caffeine for a 70-kg adult, while the lowest observed adverse effect level (LOAEL) was 770 mg (7-8 cups of coffee) for a 70-kg adult. Overall, the doses associated with possible adverse cardiovascular effects were more than either the amount of caffeine consumed over a 24-hour period in two regular energy shots (400 mg/day) or the amount in two extra strength energy shots (460 mg/day).

Considerations in deriving quantitative cancer criteria for inorganic arsenic exposure via inhalation.

The inhalation unit risk (IUR) that currently exists in the United States Environmental Protection Agency's (US EPA's) Integrated Risk Information System was developed in 1984 based on studies examining the relationship between respiratory cancer and arsenic exposure in copper smelters from two US locations: the copper smelter in Anaconda, Montana, and the American Smelting And Refining COmpany (ASARCO) smelter in Tacoma, Washington. Since US EPA last conducted its assessment, additional data have become available from epidemiology and mechanistic studies. In addition, the California Air Resources Board, Texas Commission of Environmental Quality, and Dutch Expert Committee on Occupational Safety have all conducted new risk assessments. All three analyses, which calculated IURs based on respiratory/lung cancer mortality, generated IURs that are lower (i.e., less restrictive) than the current US EPA value of 4.3×10(-3) (µg/m(3))(-1). The IURs developed by these agencies, which vary more than 20-fold, are based on somewhat different studies and use different methodologies to address uncertainties in the underlying datasets. Despite these differences, all were developed based on a cumulative exposure metric assuming a low-dose linear dose-response relationship. In this paper, we contrast and compare the analyses conducted by these agencies and critically evaluate strengths and limitations inherent in the data and methodologies used to develop quantitative risk estimates. In addition, we consider how these data could be best used to assess risk at much lower levels of arsenic in air, such as those experienced by the general public. Given that the mode of action for arsenic supports a threshold effect, and epidemiological evidence suggests that the arsenic concentration in air is a reliable predictor of lung/respiratory cancer risk, we developed a quantitative cancer risk analysis using a nonlinear threshold model. Applying a nonlinear model to occupational data, we established points of departure based on both cumulative exposure (µg/m(3)-years) to arsenic and arsenic concentration (µg/m(3)) via inhalation. Using these values, one can assess the lifetime risk of respiratory cancer mortality associated with ambient air concentrations of arsenic for the general US population.

Evaluation of Potential Exposure to Metals in Laundered Shop Towels.

We reported in 2003 that exposure to metals on laundered shop towels (LSTs) could exceed toxicity criteria. New data from LSTs used by workers in North America document the continued presence of metals in freshly laundered towels. We assessed potential exposure to metals based on concentrations of metals on the LSTs, estimates of LST usage by employees, and the transfer of metals from LST-to-hand, hand-to-mouth, and LST-to-lip, under average- or high-exposure scenarios. Exposure estimates were compared to toxicity criteria. Under an average-exposure scenario (excluding metals' data outliers), exceedances of the California Environmental Protection Agency, U.S. Environmental Protection Agency, and the Agency for Toxic Substances and Disease Registry toxicity criteria may occur for aluminum, cadmium, cobalt, copper, iron, and lead. Calculated intakes for these metals were up to more than 400-fold higher (lead) than their respective toxicity criterion. For the high-exposure scenario, additional exceedances may occur, and high-exposure intakes were up to 1,170-fold higher (lead) than their respective toxicity criterion. A sensitivity analysis indicated that alternate plausible assumptions could increase or decrease the magnitude of exceedances, but were unlikely to eliminate certain exceedances, particularly for lead.

Effects of MTBE on the reported incidence of Leydig cell tumors in Sprague-Dawley rats: range of possible Poly-3 results.

An increased Leydig cell tumor (LCT) incidence has been reported in a study of Sprague-Dawley (SD) rats exposed via gavage to 1000 (but not 250)mg/kgday MTBE; it is unclear, however, if this finding was indeed dose-related or due to the statistical analyses not having adequately accounted for the increased survival rate in the high-dose animals and/or for multiple statistical comparisons. To address this question, we conducted Hoel-Walburg and Poly-3 analyses, using p-values of 0.01 for pair-wise comparisons and 0.005 for trend tests of common tumors. We found that MTBE does not cause a statistically significant increase in LCTs in SD rats when survival is appropriately taken into account. In addition, the original study reported some overall survival data, but did not specify which rats had LCTs. This led us to conduct separate Poly-3 analyses for the most extreme scenarios of survival age and tumor incidence to provide an illustrative example of approaches for analyzing the impact of survival rates on tumor findings in the absence of animal-specific survival data. We found this method to provide results similar to analyses using the actual data, suggesting that it can be used when full survival data are not available.