The EPA Health Risk Assessment of Methylcyclopentadienyl Manganese Tricarbonyl (MMT)

This paper describes the U.S. Environmental Protection Agency's assessment of potential health risks associated with the possible widespread use of a manganese (Mn)-based fuel additive, methylcyclopentadienyl manganese tricarbonyl (MMT). This assessment was significant in several respects and may be instructive in identifying certain methodological issues of general relevance to risk assessment. A major feature of the inhalation health risk assessment was the derivation of Mn inhalation reference concentration (RfC) estimates using various statistical approaches, including benchmark dose and Bayesian analyses. The exposure assessment component used data from the Particle Total Exposure Assessment Methodology (PTEAM) study and other sources to estimate personal exposure levels of particulate Mn attributable to the permitted use of MMT in leaded gasoline in Riverside, CA, at the time of the PTEAM study; on this basis it was then possible to predict a distribution of possible future exposure levels associated with the use of MMT in all unleaded gasoline. Qualitative as well as quantitative aspects of the risk characterization are summarized, along with inherent uncertainties due to data limitations.     

Models of Neurotoxicity: Extrapolation of Benchmark Doses in Vitro

In risk assessment, no observed exposure level (NOAEL) and benchmark dose (BMD) are usually derived either from epidemiological studies in humans or from animal experiments. In many in vitro studies, concentration-effect/response curves have been analyzed using different mathematical models finalized to the identification of EC50. In the present article, we propose a model to fit dose-response curves in vitro. The BMD approach has been used to compare the cell viability (MIT assay) of different rat (C6 and PC12, glial and neuronal, respectively) and human cell lines (D384 and SK-N-MC, glial and neuronal, respectively) after 24-hour exposure to the following neurotoxic substances: manganese chloride (MnCl2), methyl-mercury (Me-Hg), and the enantiomers of styrene oxide (SO). For all rat and human cell lines, the potency of the examined compounds was: MnCl2 < S-SO < R-SO < Me-Hg. A preliminary comparison with in vivo toxicity data for these substances gave rise to consistent results. Whereas a reasonable agreement between in vitro and in vivo data has been found for Mn and styrene oxide, a wide scatter of LOAEL has been reported for Me-Hg and these appear to be either much higher or lower than the BMD for the MIT assay we observed in vitro.     

Assessment of the Effect of Population and Diary Sampling Methods on Estimation of School‐Age Children Exposure to Fine Particles

Population and diary sampling methods are employed in exposure models to sample simulated individuals and their daily activity on each simulation day. Different sampling methods may lead to variations in estimated human exposure. In this study, two population sampling methods (stratified‐random and random‐random) and three diary sampling methods (random resampling, diversity and autocorrelation, and Markov‐chain cluster [MCC]) are evaluated. Their impacts on estimated children's exposure to ambient fine particulate matter (PM_2.5) are quantified via case studies for children in Wake County, NC for July 2002. The estimated mean daily average exposure is 12.9 μg/m³ for simulated children using the stratified population sampling method, and 12.2 μg/m³ using the random sampling method. These minor differences are caused by the random sampling among ages within census tracts. Among the three diary sampling methods, there are differences in the estimated number of individuals with multiple days of exposures exceeding a benchmark of concern of 25 μg/m³ due to differences in how multiday longitudinal diaries are estimated. The MCC method is relatively more conservative. In case studies evaluated here, the MCC method led to 10% higher estimation of the number of individuals with repeated exposures exceeding the benchmark. The comparisons help to identify and contrast the capabilities of each method and to offer insight regarding implications of method choice. Exposure simulation results are robust to the two population sampling methods evaluated, and are sensitive to the choice of method for simulating longitudinal diaries, particularly when analyzing results for specific microenvironments or for exposures exceeding a benchmark of concern.     

Predicted Infant Exposure to Tetrachloroethene in Human Breastmilk

Based on a variety of maternal occupational and residential inhalation exposure scenarios, estimates of infant exposure to the dry-cleaning solvent tetrachlorothylene (perchloroethylene, PCE) in breastmilk were made. Physiologically based pharmacokinetic (PBPK) modeling indicates that infants may be exposed to elevated levels of PCE in breastmilk due to their mothers' inhalation of PCE. The PBPK-predicted breastmilk PCE concentrations agree very well with measured concentrations, where available. Based on this analysis, infants may be exposed to this workplace chemical via breastmilk at doses corresponding to rather high levels of risk. Predicted breastmilk doses provide the infant with little margin of exposure to doses associated with adverse health effects. In addition, the estimated increased cancer risks associated with these infant exposures are large under certain exposure scenarios. The actual concentrations of PCE in breastmilk of exposed mothers can only be known with certainty if monitoring is conducted. Due to the widespread exposure potential, monitoring studies should be undertaken so that the appropriate risk management alternatives can be better evaluated.     

Risk Assessment of the Carbon Nanotube Group

This study assessed the health risks via inhalation and derived the occupational exposure limit (OEL) for the carbon nanotube (CNT) group rather than individual CNT material. We devised two methods: the integration of the intratracheal instillation (IT) data with the inhalation (IH) data, and the “biaxial approach.” A four‐week IH test and IT test were performed in rats exposed to representative materials to obtain the no observed adverse effect level, based on which the OEL was derived. We used the biaxial approach to conduct a relative toxicity assessment of six types of CNTs. An OEL of 0.03 mg/m³ was selected as the criterion for the CNT group. We proposed that the OEL be limited to 15 years. We adopted adaptive management, in which the values are reviewed whenever new data are obtained. The toxicity level was found to be correlated with the Brunauer‐Emmett‐Teller (BET)‐specific surface area (BET‐SSA) of CNT, suggesting the BET‐SSA to have potential for use in toxicity estimation. We used the published exposure data and measurement results of dustiness tests to compute the risk in relation to particle size at the workplace and showed that controlling micron‐sized respirable particles was of utmost importance. Our genotoxicity studies indicated that CNT did not directly interact with genetic materials. They supported the concept that, even if CNT is genotoxic, it is secondary genotoxicity mediated via a pathway of genotoxic damage resulting from oxidative DNA attack by free radicals generated during CNT‐elicited inflammation. Secondary genotoxicity appears to involve a threshold.     

Dose-Response and Risk Assessment of Airborne Hexavalent Chromium and Lung Cancer Mortality

This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).     

A Physiologically Based Pharmacokinetic Assessment of Tetrachloroethylene in Groundwater for a Bathing and Showering Determination

A two-step methodology is described to make a health-based determination for the bathing and showering use of the water from a private well contaminated with volatile organic chemicals. The chemical perchloroethylene (PERC) is utilized to illustrate the approach. First, a chemical-specific exposure model is used to predict the concentration of PERC in the shower air, shower water, and in the air above the bathtub. Second, a physiologically based pharmacokinetic (PBPK) model is used to predict the concentration of PERC delivered to the target tissue, the brain, since the focus is on neurological endpoints. The simulation exercise includes concurrent dermal and inhalation routes of exposure. A reference target tissue level (RTTL) in the brain is estimated using the PBPK model. A hazard index based on this benchmark guideline is used to make a regulatory determination for bathing and showering use of the contaminated water.     

Methods and Rationale for Derivation of a Reference Dose for Methylmercury by the U.S. EPA

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.     

A Simulation Study of Quantitative Risk Assessment for Bivariate Continuous Outcomes

The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with binary and continuous multiple endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Yu and Catalano (2005) describe a method for quantitative risk assessment for bivariate continuous outcomes by extending a univariate method of percentile regression. The model is likelihood based and allows for separate dose‐response models for each outcome while accounting for the bivariate correlation. The approach to benchmark dose (BMD) estimation is analogous to that for quantal data without having to specify arbitrary cutoff values. In this article, we evaluate the behavior of the BMD relative to background rates, sample size, level of bivariate correlation, dose‐response trend, and distributional assumptions. Using simulations, we explore the effects of these factors on the resulting BMD and BMDL distributions. In addition, we illustrate our method with data from a neurotoxicity study of parathion exposure in rats.     

Aldrin and Dieldrin: A Reevaluation of the Cancer and Noncancer Dose‐Response Assessments

The dose‐response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg‐day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg‐day)^?1, respectively (i.e., about 5‐ and 2.3‐fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.     

Hexavalent Chromium and Lung Cancer in the Chromate Industry: A Quantitative Risk Assessment

The purpose of this investigation was to estimate excess lifetime risk of lung cancer death resulting from occupational exposure to hexavalent-chromium-containing dusts and mists. The mortality experience in a previously studied cohort of 2,357 chromate chemical production workers with 122 lung cancer deaths was analyzed with Poisson regression methods. Extensive records of air samples evaluated for water-soluble total hexavalent chromium were available for the entire employment history of this cohort. Six different models of exposure-response for hexavalent chromium were evaluated by comparing deviances and inspection of cubic splines. Smoking (pack-years) imputed from cigarette use at hire was included in the model. Lifetime risks of lung cancer death from exposure to hexavalent chromium (assuming up to 45 years of exposure) were estimated using an actuarial calculation that accounts for competing causes of death. A linear relative rate model gave a good and readily interpretable fit to the data. The estimated rate ratio for 1 mg/m3-yr of cumulative exposure to hexavalent chromium (as CrO3), with a lag of five years, was RR=2.44 (95% CI=1.54-3.83). The excess lifetime risk of lung cancer death from exposure to hexavalent chromium at the current OSHA permissible exposure limit (PEL) (0.10 mg/m3) was estimated to be 255 per 1,000 (95% CI: 109-416). This estimate is comparable to previous estimates by U.S. EPA, California EPA, and OSHA using different occupational data. Our analysis predicts that current occupational standards for hexavalent chromium permit a lifetime excess risk of dying of lung cancer that exceeds 1 in 10, which is consistent with previous risk assessments.     

Will the Occupational Safety and Health Administration's Proposed Standards for Occupational Exposure to Respirable Crystalline Silica Reduce Workplace Risk?

The Occupational Safety and Health Administration (OSHA) is developing regulations to amend existing standards for occupational exposure to respirable crystalline silica by establishing a new permissible exposure limit as well as a series of ancillary provisions for controlling exposure. This article briefly reviews OSHA's proposed regulatory approach and the statutory authority on which it is based. It then evaluates OSHA's preliminary determination of significant risk and its analysis of the risk reduction achievable by its proposed controls. It recognizes that OSHA faces multiple challenges in devising a regulatory approach that reduces exposures and health risks and meets its statutory goal. However, the greatest challenge to reducing risks associated with silica exposure is not the lack of incentives (for either employers or employees) but rather lack of information, particularly information on the relative toxicity of different forms of silica. The article finds that OSHA's proposed rule would contribute little in the way of new information, particularly since it is largely based on information that is at least a decade old—a significant deficiency, given the rapidly changing conditions observed over the last 45 years. The article concludes with recommendations for alternative approaches that would be more likely to generate information needed to improve worker health outcomes.     

Worker Exposure Standard for Phosphine Gas

The 1998 U.S. Environmental Protection Agency Office of Pesticide Programs (OPP) re-registration eligibility decision (RED) for phosphine fumigants has generated much interest in defining safe levels of exposure for workers and worker bystanders. This report summarizes the pertinent literature on phosphine toxicity, including animal inhalation studies and human epidemiology studies, and also describes a margin-of-exposure (MOE) analysis based on available worker exposure data. In addition, a safe occupational exposure limit is estimated using typical OPP assumptions, after determination of appropriate uncertainty factors, based on quality of data in the principal study and pharmacokinetic considerations. While a conservative 8-hour time-weighted average (TWA) of 0.1 ppm was calculated, the overall weight of evidence, from a risk-management perspective, supports a conclusion that an occupational TWA of 0.3 ppm provides adequate health protection. In addition, a 15-minute short-term exposure limit (STEL) of 3 ppm was estimated. Finally, in contrast to the MOE analysis described in the OPP's phosphine RED, the MOE analysis described herein does not indicate that fumigation workers are currently being exposed to unacceptable levels of phosphine. Collectively, these findings support the occupational exposure limits of 0.3 ppm (8-hour TWA) and 1 ppm (STEL) established in the updated applicator's manuals for phosphine-generating products, which recently received approval from OPP.     

Use of Environmental Tobacco Smoke Constituents as Markers for Exposure

The 16-City Study analyzed for gas-phase environmental tobacco smoke (ETS) constituents (nicotine, 3-ethenyl pyridine [3-EP], and myosmine) and for particulate-phase constituents (respirable particulate matter [RSP], ultraviolet-absorbing particulate matter [UVPM], fluorescing particulate matter [FPM], scopoletin, and solanesol). In this second of three articles, we discuss the merits of each constituent as a marker for ETS and report pair-wise comparisons of the markers. Neither nicotine nor UVPM were good predictors for RSP. However, nicotine and UVPM were good qualitative predictors of each other. Nicotine was correlated with other gas-phase constituents. Comparisons between UVPM and other particulate-phase constituents were performed. Its relation with FPM was excellent, with UVPM approximately 1 1/2 times FPM. The correlation between UVPM and solanesol was good, but the relationship between the two was not linear. The relation between UVPM and scopoletin was not good, largely because of noise in the scopoletin measures around its limit of detection. We considered the relation between nicotine and saliva cotinine, a metabolite of nicotine. The two were highly correlated on the group level. That is, for each cell (smoking home and work, smoking home but nonsmoking work, and so forth), there was high correlation between average cotinine and 24-hour time-weighted average (TWA) nicotine concentrations. However, on the individual level, the correlations, although significant, were not biologically meaningful. A consideration of cotinine and nicotine or 3-EP on a subset of the study whose only exposure to ETS was exclusively at work or exclusively at home showed that home exposure was a more important source of ETS than work exposure.     

Computerized Estimates of Potential Occupational Health Risk Due to Chemical Exposure

Estimating the potential health risk encountered by workers due to their exposure to various chemicals is enormously complex, since many chemicals may be involved and each may have multiple toxic effects. As an aid to this estimation process, a computer program, or model, which computes index numbers expressing the relative health risk of occupational groups due to their potential chemical exposures was developed at the National Institute for Occupational Safety and Health (NIOSH). This model considers an inventory of the chemicals to which specific occupational groups are potentially exposed, the published information regarding the toxic effects of each chemical, and the conditions of occupational exposure. The system then develops indices of potential occupational group health risk by considering weighted combinations of eight distinct health effects. No direct comparison with external occupational risk indices is currently possible, but internal testing of the model reveals no obvious inconsistencies.     

Computerized Estimates of Potential Occupational Health Risk Due to Chemical Exposure

Estimating the potential health risk encountered by workers due to their exposure to various chemicals is enormously complex, since many chemicals be involved and each may have multiple toxic effects. As an aid to this estimation process, a computer program, or model, which computes index numbers expressing the relative health risk of occupational groups due to their potential chemical exposures was developed at the National Institute for Occupational Safety and Health (NIOSH). This model considers an inventory of the chemicals to which specific occupational groups are potentially exposed, the published information regarding the toxic effects of each chemical, and the conditions of occupational exposure. The system then develops indices of potential occupational group health risk by considering weighted combinations of eight distinct health effects. No direct comparison with external occupational risk indices is currently possible, but internal testing of the model reveals no obvious inconsistencies.     

Comparative Risks of Cancer from Drywall Finishing Based on Stochastic Modeling of Cumulative Exposures to Respirable Dusts and Chrysotile Asbestos Fibers

Sanding joint compounds is a dusty activity and exposures are not well characterized. Until the mid 1970s, asbestos‐containing joint compounds were used by some people such that sanding could emit dust and asbestos fibers. We estimated the distribution of 8‐h TWA concentrations and cumulative exposures to respirable dusts and chrysotile asbestos fibers for four worker groups: (1) drywall specialists, (2) generalists, (3) tradespersons who are bystanders to drywall finishing, and (4) do‐it‐yourselfers (DIYers). Data collected through a survey of experienced contractors, direct field observations, and literature were used to develop prototypical exposure scenarios for each worker group. To these exposure scenarios, we applied a previously developed semi‐empirical mathematical model that predicts area as well as personal breathing zone respirable dust concentrations. An empirical factor was used to estimate chrysotile fiber concentrations from respirable dust concentrations. On a task basis, we found mean 8‐h TWA concentrations of respirable dust and chrysotile fibers are numerically highest for specialists, followed by generalists, DIYers, and bystander tradespersons; these concentrations are estimated to be in excess of the respective current but not historical Threshold Limit Values. Due to differences in frequency of activities, annual cumulative exposures are highest for specialists, followed by generalists, bystander tradespersons, and DIYers. Cumulative exposure estimates for chrysotile fibers from drywall finishing are expected to result in few, if any, mesothelioma or excess lung cancer deaths according to recently published risk assessments. Given the dustiness of drywall finishing, we recommend diligence in the use of readily available source controls.     

Target Levels—Tools for Prevention

Although occupational exposure limits are sought to establish health-based standards, they do not always give a sufficient basis for planning an indoor air climate that is good and comfortable for the occupants in industrial work rooms. This paper considers methodologies by which the desired level, i.e., target level, of air quality in industrial settings can be defined, taking into account feasibility issues. Risk assessment based on health criteria is compared with risk-assessment based on "Best Available Technology" (BAT). Because health-based risk estimates at low concentration regions are rather inaccurate, the technology-based approach is emphasized. The technological approach is based on information on the prevailing concentrations in industrial work environments and the benchmark air quality attained with the best achievable technology. The prevailing contaminant concentrations are obtained from a contaminant exposure databank, and the benchmark air quality by field measurements in industrial work rooms equipped with advanced ventilation and production technology. As an example, the target level assessment has been applied to formaldehyde, total inorganic dust and hexavalent chromium, which are common contaminants in work room air.     

Derivation of Noncancer Reference Values for Acrylonitrile

Dose‐response assessments were conducted for the noncancer effects of acrylonitrile (AN) for the purposes of deriving subchronic and chronic oral reference dose (RfD) and inhalation reference concentration (RfC) values. Based upon an evaluation of available toxicity data, the irritation and neurological effects of AN were determined to be appropriate bases for deriving reference values. A PBPK model, which describes the toxicokinetics of AN and its metabolite 2‐cyanoethylene oxide (CEO) in both rats and humans, was used to assess the dose‐response data in terms of an internal dose measure for the oral RfD values, but could not be used in deriving the inhalation RfC values. Benchmark dose (BMD) methods were used to derive all reference values. Where sufficient information was available, data‐derived uncertainty factors were applied to the points of departure determined by BMD methods. From this assessment, subchronic and chronic oral RfD values of 0.5 and 0.05 mg/kg/day, respectively, were derived. Similarly, subchronic and chronic inhalation RfC values of 0.1 and 0.06 mg/m³, respectively, were derived. Confidence in the reference values derived for AN was considered to be medium to high, based upon a consideration of the confidence in the key studies, the toxicity database, dosimetry, and dose‐response modeling.     

Improving Risk Assessment Calculations for Traditional Foods Through Collaborative Research with First Nations Communities

As industrial development is increasing near northern Canadian communities, human health risk assessments (HHRA) are conducted to assess the predicted magnitude of impacts of chemical emissions on human health. One exposure pathway assessed for First Nations communities is the consumption of traditional plants, such as muskeg tea (Labrador tea) (Ledum/Rhododendron groenlandicum) and mint (Mentha arvensis). These plants are used to make tea and are not typically consumed in their raw form. Traditional practices were used to harvest muskeg tea leaves and mint leaves by two First Nations communities in northern Alberta, Canada. Under the direction of community elders, community youth collected and dried plants to make tea. Soil, plant, and tea decoction samples were analyzed for inorganic elements using inductively coupled plasma‐mass spectrometry. Concentrations of inorganic elements in the tea decoctions were orders of magnitude lower than in the vegetation (e.g., manganese 0.107 mg/L in tea, 753 mg/kg in leaves). For barium, the practice of assessing ingestion of raw vegetation would have resulted in a hazard quotient (HQ) greater than the benchmark of 0.2. Using measured tea concentrations it was determined that exposure would result in risk estimates orders of magnitude below the HQ benchmark of 0.2 (HQ = 0.0049 and 0.017 for muskeg and mint tea, respectively). An HHRA calculating exposure to tea vegetation through direct ingestion of the leaves may overestimate risk. The results emphasize that food preparation methods must be considered when conducting an HHRA. This study illustrates how collaboration between Western scientists and First Nations communities can add greater clarity to risk assessments.