Risk characterization of N-nitrosodimethylamine in pharmaceuticals.

Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD50 identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.

Measured removal rates of chrysotile asbestos fibers from air and comparison with theoretical estimates based on gravitational settling and dilution ventilation.

CONTEXT: Industrial hygiene assessments often focus on activity-based airborne asbestos concentration measurements, but few empirical data exist regarding the fiber removal rate from air after activities cease. OBJECTIVE: Grade 7T chrysotile indoor fiber settling (FS) rates were characterized using air sampling (NIOSH Method 7402). MATERIALS AND METHODS: Six replicate events were conducted in a 58 m(3) study chamber (ventilation 3.5 ACH), in which chrysotile-contaminated work clothing was manipulated for 15 min followed by 30 min of no activity. The fiber concentration decay constant and removal rate were characterized using an exponential decay model based on the measurements. RESULTS: Breathing zone airborne chrysotile concentrations decreased by 86% within 15-30 min after fiber disturbance, compared to concentrations during active disturbance (p < 0.05). Estimated mean time required for 99% of the phase contrast microscopy-equivalent (PCME) fibers to be removed from air was approximately 30 min (95% CI: 22-57 min). The observed effective FS velocity was 0.0034 m/s. This settling velocity was between 4.5-fold and 180-fold faster than predicted by two different particulate gravitational settling models. Additionally, PCME concentrations decreased approximately 2.5-fold faster than predicted due to air exchange alone (32 versus 79 min to 99% decrease in concentration). DISCUSSION: Other measurement studies have reported similar airborne fiber removal rates, supporting the finding that factors other than gravitational settling and dilution ventilation contribute measurably to PCM fiber removal from air (e.g. impaction, agglomeration). CONCLUSION: Overall, the scientific weight of evidence indicates that the time necessary for removal of 99% of fibers greater than 5 µm in length (with aspect ratios greater than 3:1) is approximately 20-80 min.

Evaluation of take-home exposure and risk associated with the handling of clothing contaminated with chrysotile asbestos.

The potential for para-occupational (or take-home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take-home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take-home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0-0.1 fibers per cubic centimeter [f/cc], 1-2 f/cc, and 2-4 f/cc; two events each for 31-43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30-minute clothes-handling and shake-out events were conducted, each including 15 minutes of active handling (15-minute means; 0.014-0.097 f/cc) and 15 additional minutes of no handling (30-minute means; 0.006-0.063 f/cc). Percentages of personal clothes-handling TWAs relative to clothes-loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes-handling activity. Airborne concentrations for the clothes handler were 0.2-1.4% (eight-hour TWA or daily ratio) and 0.03-0.27% (40-hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take-home or ambient doses: 0.00044-0.105 f/cc year).

An analysis of workplace exposures to benzene over four decades at a petrochemical processing and manufacturing facility (1962-1999).

Benzene, a known carcinogen, can be generated as a by-product during the use of petroleum-based raw materials in chemical manufacturing. The aim of this study was to analyze a large data set of benzene air concentration measurements collected over nearly 40 years during routine employee exposure monitoring at a petrochemical manufacturing facility. The facility used ethane, propane, and natural gas as raw materials in the production of common commercial materials such as polyethylene, polypropylene, waxes, adhesives, alcohols, and aldehydes. In total, 3607 benzene air samples were collected at the facility from 1962 to 1999. Of these, in total 2359 long-term (>1 h) personal exposure samples for benzene were collected during routine operations at the facility between 1974 and 1999. These samples were analyzed by division, department, and job title to establish employee benzene exposures in different areas of the facility over time. Sampling data were also analyzed by key events over time, including changes in the occupational exposure limits (OELs) for benzene and key equipment process changes at the facility. Although mean benzene concentrations varied according to operation, in nearly all cases measured benzene quantities were below the OEL in place at the time for benzene (10 ppm for 1974-1986 and 1 ppm for 1987-1999). Decreases in mean benzene air concentrations were also found when data were evaluated according to 7- to 10-yr periods following key equipment process changes. Further, an evaluation of mortality rates for a retrospective employee cohort (n = 3938) demonstrated that the average personal benzene exposures at this facility (0.89 ppm for the period 1974-1986 and 0.125 ppm for the period 1987-1999) did not result in increased standardized mortality ratio (SMRs) for diseases or malignancies of the lymphatic system. The robust nature of this data set provides comprehensive exposure information that may be useful for assessing human benzene exposures at similar facilities. The data also provide a basis for comparable measured exposure levels and the potential for adverse health effects. These data may also prove beneficial for comparing relative exposure potential for production versus nonproduction operations and the relationship between area and personal breathing zone samples.

An evidence-based analysis of epidemiologic associations between lymphatic and hematopoietic cancers and occupational exposure to gasoline.

The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence-based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene.

Airborne asbestos concentrations associated with heavy equipment brake removal.

Asbestos-containing brake linings were used in heavy-duty construction equipment such as tractors, backhoes, and bulldozers prior to the 1980s. While several published studies have evaluated exposures to mechanics during brake repair work, most have focused on automobiles and light trucks, not on heavy agricultural or construction vehicles. The purpose of this study is to characterize the airborne concentration of asbestos to workers and bystanders from brake wear debris during brake removal from 12 loader/backhoes and tractors manufactured between 1960 and 1980. Asbestos content in brake lining (average 20% chrysotile by polarized light microscopy) and brake wear debris [average 0.49% chrysotile by transmission electron microscopy (TEM)] was also quantified. Breathing zone samples on the lapel of mechanics (n = 44) and area samples at bystander (n = 34), remote (n = 22), and ambient (n = 12) locations were collected during 12 brake changes and analyzed using phase contrast microscopy (PCM) [National Institute for Occupational Safety and Health (NIOSH) 7400] and TEM (NIOSH 7402). In addition, the fiber distribution by size and morphology was evaluated according to the International Organization for Standardization method for asbestos. Applying the ratio of asbestos fibers:total fibers (including non-asbestos) as determined by TEM to the PCM results, the average airborne chrysotile concentrations (PCM equivalent) were 0.024 f/cc for the mechanic and 0.009 f/cc for persons standing 1.2-3.1 m from the activity during the period of exposure ( approximately 0.5 to 1 h). Considering the time involved in the activity, and assuming three brake jobs per shift, these results would convert to an average 8-h time-weighted average of 0.009 f/cc for a mechanic and 0.006 f/cc for a bystander. The results indicate that (i) the airborne concentrations for worker and bystander samples were significantly less than the current occupational exposure limit of 0.1 f/cc; (ii) approximately 2% of respirable fibers were >20 microm in length; and (iii) approximately 95% of chrysotile in the brake linings degraded in the friction process. The industrial hygiene data presented here should be useful for conducting retrospective and current exposure assessments of individuals, as well as hazard assessments of work activities that involve repairing and replacing asbestos-containing brakes in heavy construction equipment.

Historical analysis of airborne beryllium concentrations at a copper beryllium machining facility (1964-2000).

Copper beryllium alloys are the most commonly used form of beryllium; however, there have been few studies assessing occupational exposure in facilities that worked exclusively with this alloy versus those where pure metal or beryllium oxide may also have been present. In this paper, we evaluated the airborne beryllium concentrations at a machining plant using historical industrial hygiene samples collected between 1964 and 2000. With the exception of a few projects conducted in the 1960s, it is believed that >95% of the operations used copper beryllium alloy exclusively. Long-term (>120 min) and short-term (<120 min) personal and area samples were collected during a variety of activities including machining of copper beryllium-containing parts, as well as finishing operations (e.g., deburring and polishing) and decontamination of machinery. A total of 580 beryllium air samples were analyzed (311 personal and 269 area samples). The average concentration based on area samples (1964-2000) was 0.021 microg m(-3) (SD 0.17 microg m(-3); range 0.00012-2.5 microg m(-3)); 68.8% were below the analytical limit of detection (LOD). The average airborne beryllium concentration, based on all personal samples available from 1964 through the end of 2000 (n = 311), was 0.026 microg m(-3) (SD 0.059 microg m(-3); range 0.019-0.8 microg m(-3)); 97.4% were below the LOD. Personal samples collected from machinists (n = 78) had an average airborne concentration of 0.021 microg m(-3) (SD 0.014 microg m(-3); range 0.019-0.14 microg m(-3)); 97.4% were below the LOD. Airborne concentrations were consistently below the Occupational Safety and Health Administration permissible exposure limit for beryllium (2 microg m(-3)). Overall, the data indicate that for machining operations involving copper beryllium, the airborne concentrations for >95% of the samples were below the contemporaneous occupational exposure limits or the 1999 Department of Energy action level of 0.2 microg m(-3) and, in most cases, were below the LOD.

Exposure to chrysotile asbestos associated with unpacking and repacking boxes of automobile brake pads and shoes.

Industrial hygiene surveys and epidemiologic studies of auto mechanics have shown that these workers are not at an increased risk of asbestos-related disease; however, concerns continue to be raised regarding asbestos exposure from asbestos-containing brakes. Handling new asbestos-containing brake components has recently been suggested as a potential source of asbestos exposure. A simulation study involving the unpacking and repacking of 105 boxes of brakes (for vehicles ca. 1946-80), including 62 boxes of brake pads and 43 boxes of brake shoes, was conducted to examine how this activity might contribute to both short-term and 8-h time-weighted average exposures to asbestos. Breathing zone samples on the lapel of a volunteer worker (n = 80) and area samples at bystander (e.g., 1.5 m from worker) (n = 56), remote area (n = 26) and ambient (n = 10) locations collected during the unpacking and repacking of boxes of asbestos-containing brakes were analyzed by phase contrast microscopy and transmission electron microscopy. Exposure to airborne asbestos was characterized for a variety of parameters including the number of boxes handled, brake type (i.e. pads versus shoes) and the distance from the activity (i.e. worker, bystander and remote area). This study also evaluated the fiber size and morphology distribution according to the International Organization for Standardization analytical method for asbestos. It was observed that (i) airborne asbestos concentrations increased with the number of boxes unpacked and repacked, (ii) handling boxes of brake pads resulted in higher worker asbestos exposures compared to handling boxes of brake shoes, (iii) cleanup and clothes-handling tasks produced less airborne asbestos than handling boxes of brakes and (iv) fiber size and morphology analysis showed that while the majority of fibers were free (e.g. not associated with a cluster or matrix), <30% were respirable and even fewer were of the size range (>20 microm length) considered to pose the greatest risk of asbestos-related disease. It was found that average airborne chrysotile concentrations (30 min) ranged from 0.086 to 0.368 and 0.021 to 0.126 f cc(-1) for a worker unpacking and repacking 4-20 boxes of brake pads and 4-20 boxes of brake shoes, respectively. Additionally, average airborne asbestos exposures (30 min) at bystander locations ranged from 0.004 to 0.035 and 0.002 to 0.011 f cc(-1) when 4-20 boxes of brake pads and 4-20 boxes of brake shoes were handled, respectively. These data show that a worker handling a relatively large number of boxes of brakes over short periods of time will not be exposed to airborne asbestos in excess of its historical or current short-term occupational exposure limits.

Assessment of potential human health risks posed by benzene in beverages.

A recent study by the U.S. Food and Drug Administration (FDA) indicated that some beverages contained benzene at levels above the federal drinking water standard of 5 parts per billion (ppb). In tests conducted by the FDA, Crystal Light Sunrise Classic Orange (CLSCO) was reported to contain benzene levels as high as 87.9 ppb. The purpose of the present study was to better characterize benzene concentrations in CLSCO and to quantify potential human health risks. Twenty-eight samples of CLSCO were obtained from retail stores in Houston, Tex., U.S.A. The mean benzene concentrations in 16 oz original and new formulation bottles were 90 and 0.18 ppb, respectively, while 64-oz bottles contained an average of 3.38 ppb. A variety of exposure scenarios were evaluated to determine potential health risks using both deterministic and probabilistic techniques. In the deterministic analyses, upper bound point estimate cancer risks ranged from 5.4E-6 to 8.7E-8, while hazard indices (HI) ranged from 0.28 to 0.00104. Probabilistic analyses were conducted to develop more realistic cancer risk estimates. In these analyses, the 50th and 95th percentile cancer risk estimates were 3.7E-6 and 8.0E-6, and the 50th and 95th percentile hazard indices were 0.19 and 0.42, respectively. In conclusion, all cancer risk estimates and noncancer hazards met the typical health risk benchmarks established by the U.S. regulatory agencies (1E-4 to 1E-6 for cancer and hazard indices less than 1.0).

DNA-protein cross-link formation in Burkitt lymphoma cells cultured with benzaldehyde and the sedative paraldehyde.

Exposure to aldehydes represents potential risks to human and animal health. Cyclic aldehydes such as benzaldehyde, 2-furaldehyde, and paraldehyde were found to induce formation of stable DNA-protein cross-links (DPXs) in cultured human lymphoma cells. A relationship between increased cytotoxicity and DPX formation was observed with each aldehyde. Paraldehyde is a sedative drug used predominately in treatment of ethanol withdrawal. Paraldehyde was the most potent cross-linking aldehyde studied, yet least cytotoxic. Although DPX formation by aliphatic aldehydes is well-known, this study confirms the potential for cyclic aldehydes to cause formation of DPXs in cultured cells at therapeutically relevant doses.

Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients.

Half-life estimates of three polychlorodibenzofurans (PCDFs) were calculated using serial blood samples collected over a 15 to 19-year period. Blood fat PCDFs were modeled in eight individuals who were exposed to contaminated rice oil in Japan (Yusho, n = 5) and in Taiwan (Yucheng, n = 3). The elimination kinetics of PCDFs were concentration-dependent, with faster rates observed at higher concentrations and the apparent transition to slower rates occurring at about 1-3 ppb. Average half-lives of 1.1, 2.3, and 1.5 years above the transition concentration and 7.2, 5.7, and 3.5 years below it were estimated for 2,3,4,7,8-pentaCDF, 1,2,3,4,7,8-hexaCDF, and 1,2,3,4,6,7,8-heptaCDF, respectively. A positive linear correlation of half-life with age was observed for the combined group, with a rate of increase of 0.19, 0.12, and 0.05-year half-life per year of increase in age for penta-, hexa-, and hepta-CDF, respectively. The distinctly younger Yucheng patients exhibited far lower variability in half-lives and age-related trends that were quite consistent with the corresponding data on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for younger persons exposed in the Seveso incident. These age- and concentration-dependent half-lives for PCDFs may have important risk assessment implications for estimating body burdens. The current study provides limited additional evidence that PCDFs, like TCDD, are more rapidly eliminated in younger individuals.

Estimating historical occupational exposure to airborne hexavalent chromium in a chromate production plant: 1940--1972.

This article presents a retrospective exposure assessment for 493 workers who were occupationally exposed to airborne hexavalent chromium, Cr(VI), at a Painesville, Ohio, chromate production plant from 1940-1972. Exposure estimates were reconstructed using a job-exposure matrix approach that related job titles with area monitoring data from 21 industrial hygiene surveys conducted from 1943 to 1971. No personal monitoring data were collected. Specifically, airborne Cr(VI) concentration profiles for 22 areas of the plant, termed job-exposure group (JEG) areas, were constructed for three distinct time periods (1940-1949, 1950-1964, and 1965-1972), with cut points based on known major plant and process changes. Average airborne Cr(VI) concentrations were the highest for the bridge crane operators (5.5 mg/m3) prior to 1965, although only four cohort members held this job title. Airborne concentrations for the rest of the production areas of the plant ranged from 1.9 mg/m3 for packers in the 1940s to 0.012 mg/m3 for ore mill operators after 1964. For nearly all JEG areas, exposures decreased over time, particularly after 1964. For example, average airborne concentrations in production areas of the plant decreased from 0.72 mg/m3 in the 1940s to 0.27 mg/m3 from 1950 to 1964, and the average was 0.039 mg/m3 after 1964. Former workers were interviewed to determine activity patterns in the plant by job title. This information was combined with Cr(VI) monitoring data to calculate cumulative occupational exposure for each worker. Cumulative exposures ranged from 0.003 to 23 (mg/m3) x years. The highest monthly 8-hour average exposure concentration for each worker ranged from 0.003 to 4.1 mg/m3. These exposure estimates have been combined with mortality data for this cohort to assess the lung cancer risk associated with inhaled Cr(VI), and a positive dose-response relationship was observed for increases in lung cancer mortality with measures of cumulative exposure and highest monthly exposure.

Workplace airborne hexavalent chromium concentrations for the Painesville, Ohio, chromate production plant (1943-1971).

Hexavalent chromium [Cr(VI)] is recognized as an inhalation carcinogen, based primarily on the increased incidence of lung cancer among occupationally exposed workers. To assess the carcinogenic potency of Cr(VI), both the U.S. Environmental Protection Agency and the Occupational Safety and Health Administration have relied on data from a 1930s cohort of workers from the Painesville, Ohio, chromate production plant. However, the exposure information for this cohort has several shortcomings. In an effort to provide better exposure information, we present here recently identified historical exposure data for the Painesville workers. More than 800 measurements of airborne Cr(VI) from 23 newly identified surveys conducted from 1943 to 1971 are presented. The results indicate that the highest Cr(VI) concentrations recorded at the plant occurred in shipping (e.g., bagging of dichromate), lime and ash, and filtering operations, with maximum yearly average Cr(VI) concentrations of 8.9, 2.7, and 2.3 mg/m(3), respectively. The locker rooms, laboratory, maintenance shop, and outdoor raw liquor storage areas had the lowest average Cr(VI) air concentrations over time, with yearly average concentrations that rarely exceeded the historical and current Threshold Limit Value TLV(R) of 0.05 mgCr(VI)/m(3) (0.1 mgCrO(3)/m(3)). Concentrations generally decreased in the plant over time. The average airborne concentration of Cr(VI) in the indoor operating areas of the plant in the 1940s was 0.72 mg/m(3), that from 1957 through 1964 was 0.27 mg/m(3), and that from 1965 through 1972 was 0.039 mg/m(3). Although in some ways limited, these data are of sufficient quality to allow for exposure reconstruction for workers employed at this plant from 1940 to 1972, and to provide the basis for an improved cancer risk assessment.

Oral bioaccessibility of dioxins/furans at low concentrations (50-350 ppt toxicity equivalent) in soil.

Animal studies have indicated that the oral bioavailability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in environmentally contaminated soil could range from 0.5 to 60%. To estimate the oral bioavailability of TCDD, and the 16 other 2,3,7,8-substituted dioxin/furan congeners, this study used a physiologically based extraction test, designed around the anatomic and physiologic characteristics of the human digestive tract. This test measures the fraction of dioxins/furans in soil that would be solubilized in the gastrointestinal tract (i.e., that would be bioaccessible) and therefore available for absorption. Eight soils from Midland, MI, were evaluated in this study and exhibited TCDD concentrations of 1.7-139 pg/g (ppt) and total TEQ concentrations of 6-340 ppt. Bioaccessibility of dioxins/furans from these soils ranged from 19 to 34% averaged across the 17 2,3,7,8-substituted dioxin/furan congeners), with an average of 25%. The total organic carbon in these soils was low--ranging from 1 to 4%--particularly for the soil series from which they were collected. Bioaccessibility of individual congeners did not appear to be correlated with degree of chlorination. Even though these dioxin/furan concentrations are much less than studied previously, these results are consistent with those from animal studies at other sites, which have generally yielded values of 20-60% relative bioavailability for TCDD in soil.

Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.

Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.

Identifying an apppropriate occupational exposure limit (OEL) for beryllium: data gaps and current research initiatives.

The occupational exposure limit of 2.0 microg/m3 for beryllium has been used in the workplace since the late 1940s. In particular, the adequacy of the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) for beryllium has recently come into question. The symposium "Beryllium: Effect on Worker Health" was convened in September 1999, to bring together leading scientists to present and discuss current research activities on beryllium exposure and chronic beryllium disease (CBD). One of the key questions to be resolved at the symposium was, "Is there a sufficient understanding of exposure and the cause of CBD that would allow us to develop a TLV that we believe would prevent disease?" Seven scientists presented information regarding the current understanding of the disease, possible causes, and ongoing research. The topics were (1) biomonitoring approaches and their relationship with clinical effects, (2) historical and current exposure assessments, (3) sampling methods and aerosol characterization, and (4) epidemiology. Six basic hypotheses regarding the relationship between exposure to beryllium and CBD were generated from the information presented at the symposium. The six hypotheses that are related to issues such as beryllium form, particle size, industrial hygiene practices, extrapulmonary routes of exposure, and genetic susceptibility also appear to be the focus of ongoing and likely future research initiatives. This article summarizes both the presentations made at the meeting and the hypotheses generated. It is expected that an understanding of these issues should explain the inconsistent dose-response relationship observed between exposure and CBD. The ongoing and planned research is anticipated to provide sufficient data within two to three years to develop one or more scientifically sound TLVs for the different chemical forms of beryllium.

Contribution of incidental exposure pathways to total beryllium exposures.

Beryllium manufacturing processes are associated with the immune-mediated chronic beryllium disease (CBO). Recent workplace epidemiological studies have been relatively unsuccessful in correlating disease with workplace air concentrations of beryllium, thereby failing to support the hypothesis that dose by the respiratory route determines the risk of disease. This has led to consideration of the hypotheses that dermal or oral exposures to beryllium can influence disease risk, either as a cause of sensitization or to induced tolerance to beryllium. If so, the control of dermal and/or ingestion exposure to beryllium, which has heretofore been widely disregarded in the United States, would be of practical importance. Most of the literature of the past 50 years indicates that ingestion and dermal uptake of beryllium are unimportant routes of exposures. The toxicology data generally support this position. However, research is under way to determine whether sensitization to beryllium may occur following exposure via routes other than inhalation, raising the question of whether this sensitization from other routes of exposure makes the lungs more susceptible to inflammation when inhaled doses are encountered. Using published data on other metals, this article describes the likely range of doses that a worker might incur in the workplace due to incidental exposure pathways (i.e., exposures not directly related to inhalation of workplace air), such as hand-to-mouth exposure, dermal contact, and resuspension following deposition of beryllium onto clothing. This analysis indicates that these incidental routes of exposure could contribute to total absorbed doses of beryllium that exceed simple airborne inhalation exposures. Because the doses presented by these alternative exposure pathways could be appreciable compared with the airborne inhaled dose, and could continue even when respirators are worn, these pathways may represent the primary routes of entry of beryllium into the body. We believe that the potential for exposure from these incidental exposure pathways merits additional study.

A comparison and critique of historical and current exposure assessment methods for beryllium: implications for evaluating risk of chronic beryllium disease.

The primary beryllium industry has generated a large amount of data on airborne beryllium concentrations that has been used to characterize exposure by task-specific activities, job category, individual worker, and processing area using a variety of methods. These methods have included high-volume breathing zone sampling, high-volume process sampling, high- and low-volume respirable and area sampling, real-time monitoring, and personal sampling. Many of the beryllium studies have used these air sampling methods to assess inhalation exposure and chronic beryllium disease (CBD) risk to beryllium; however, available data do not show a consistent dose-response relationship between airborne concentrations of beryllium and the incidence of CBD. In this article, we describe the air sampling and exposure assessment methods that have been used, review the studies that have estimated worker exposures, discuss the uncertainties associated with the level of beryllium for which these studies have reported an increased risk of CBD, and identify future investigative exposure assessment strategies. Our evaluation indicated that studies of beryllium workers are often not directly comparable because they (1) used a variety of exposure assessment methods that are not necessarily representative of individual worker exposures, (2) rarely considered respirator use, and (3) have not evaluated changes in work practices. It appears that the current exposure metric for beryllium, total beryllium mass, may not be an appropriate measurement to predict the risk of CBD. Other exposure metrics such as mass of respirable particles, chemical form, and particle surface chemistry may be more related to the prevalence of CBD than total mass of airborne beryllium mass. In addition, assessing beryllium exposure by all routes of exposure (e.g., inhalation, dermal uptake, and ingestion) rather than only inhalation exposure in future studies may prove useful.