Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment.

Physiologically based pharmacokinetic model for humans orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.

Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in rats and mice following long-term oral exposure. Model compartments were included for GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone, and a combined compartment for remaining tissues. Data from ex vivo Cr(VI) reduction studies were used to characterize reduction of Cr(VI) in fed rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue time-course data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats, consistent with small intestinal tumor formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma chromium ratios suggest that Cr(VI) entered portal circulation at drinking water concentrations equal to and greater than 60 mg/L in rodents. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. Overall, the PBPK model provides a good description of chromium toxicokinetics, with model predictions for tissue chromium within a factor of 3 for greater than 80% of measurements evaluated. The tissue data and PBPK model predictions indicate a concentration gradient in the small intestines (duodenum > jejunum > ileum), which will be useful for assessing the tumor response gradient observed in mouse small intestines in terms of target tissue dose. The rodent PBPK model presented here, when used in conjunction with a human PBPK model for Cr(VI), should provide a more robust characterization of species differences in toxicokinetic factors for assessing the potential risks associated with low-dose exposures of Cr(VI) in human populations.

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.

An environmental hazard assessment of low-level dermal exposure to hexavalent chromium in solution among chromium-sensitized volunteers.

To evaluate the potential for elicitation of allergic contact dermatitis from contact with standing water in the environment, 26 persons known to be allergic to hexavalent chromium [Cr(VI)] were exposed to 25 to 29 mg/L Cr(VI) by immersion of one arm for 30 minutes per day on 3 consecutive days in a potassium dichromate bath. Sixteen of the 26 volunteers demonstrated either no or an equivocal response to the Cr(VI) challenge. Ten of the volunteers developed a few papules or vesicles (1 to approximately 15), mild redness, and pruritus on the Cr(VI)-challenged arm. Histopathological examination of the papules revealed spongiosis and perieccrine and perivascular inflammation. The responses were diagnosed as acute perieccrine reactions. It was concluded that exposure to similar concentrations of Cr(VI) in the environment does not pose an allergic contact dermatitis hazard, even to Cr-sensitized persons.

The prevalence of chromium allergy in the United States and its implications for setting soil cleanup: a cost-effectiveness case study.

Hexavalent chromium [Cr(VI)] elicits allergic contact dermatitis (ACD) among previously sensitized individuals, and some regulatory agencies have suggested the need for Cr(VI) soil standards that are protective of this health end point. To assess the cost effectiveness of implementing ACD-based standards, it is necessary to understand the prevalence of Cr(VI) sensitivity in the general population. More than 30 published studies from 1950 to 1997 were reviewed to determine the prevalence of Cr(VI) sensitivity. No random survey of the general United States (U.S.) population has been performed to date, but the prevalence of Cr(VI) sensitization among North American clinical cohorts (e.g., patients of dermatological clinics) was reported to be 1% in 1996. The prevalence of Cr(VI) sensitivity among the general U.S. population is estimated to be 0.08%. This estimate was calculated by dividing the current U.S. clinical prevalence estimate (1%) by the ratio of Cr(VI) sensitization in clinical vs general populations in The Netherlands (12). A retrospective cost/benefit analysis for sites in Jersey City, New Jersey, suggests that remediation of soils to protect against elicitation of ACD in sensitized individuals is not a cost-effective use of public health resources.

Preliminary assessment of PCB risks to human and ecological health in the lower Passaic River.

Concentrations of Aroclor mixtures and specific polychlorinated biphenyl (PCB) congeners were measured in surface sediments and aquatic biota (striped bass fillet, mummichog, and blue crab muscle and hepatopancreas) collected from the lower Passaic River. Several of the 47 surface sediment samples contained Aroclor concentrations that exceeded a National Oceanic and Atmospheric Administration (NOAA) benchmark level for "total PCBs" (22.7 micrograms/kg). Each of the 18 PCB congeners analyzed in aquatic biota was detected in one or more tissue samples, and numerous congeners were detected in every sample (IUPAC numbers 77, 105, 114, 118, 123, 126, 156, 157, 167, and 189). PCB congener concentrations were similar to those that have been reported in fish from other waterways that contain elevated levels of PCBs. Congener 118 was present at the highest concentration in almost all samples, and constituted 14-60% of the total PCB mass (sum of all congener masses) measured in any given tissue sample. In spite of the prevalence of PCB congeners in biota tissues (up to 1314 micrograms/kg total PCBs), Aroclors were not detected in bass or crab samples at a limit of detection of 33-55 micrograms/kg. This anomaly may be due to selective degradation of certain PCB congeners that are used to analytically recognize and quantitate Aroclors. Using the measured sediment concentrations, a food web model accurately predicted blue crab muscle concentrations of individual PCB congeners (typically within a factor of two) and was also fairly accurate for mummichog (typically within an order of magnitude). Concentrations in striped bass fillet were underestimated by factors of approximately 20-140. Increased cancer risk estimates associated with fish and crab consumption were obtained using four different methods. Using Aroclor tissue concentrations (one-half the limit of detection) and an Aroclor slope factor, total risks were 2.6 x 10(-6); using the "total PCB" measurements and an Aroclor slope factor, total risks were 1.9 x 10(-5); the "PCB-TEQ" method yielded total risks of 6.5 x 10(-4); and USEPA's recent suggested approach for evaluating "dioxin-like" and non-"dioxin-like" effects resulted in a total risk of 6.6 x 10(-4). This wide range in risk estimates indicates that it is critical to the risk management decision-making process that data requirements and risk assessment objectives be carefully evaluated early in the investigation process.

Urinary chromium as a biological marker of environmental exposure: what are the limitations?

Public concern has mounted recently about environmental exposures to chromium in soil, tap water, and ambient air. In response, agencies charged with protecting public health have attempted to study exposure by monitoring urinary chromium levels among potentially exposed populations. While urinary biomonitoring of occupationally exposed workers has been successfully used to assess high-level inhalation exposures in the workplace, evaluating low-level environmental exposures has been problematic. Due to these problems, before an extensive biological monitoring study is conducted of those exposed to low levels of environmental chromium, several issues must be resolved. First, exposures to chromium must occur at the same time as sampling, because the biological half-life of chromium in urine is very short (less than 2 days). Second, reduced bioavailability and bioaccessibility via the oral and dermal routes of exposure limit the capacity of urinary monitoring to measure environmental exposures (e.g., systemic dose is too small to be measured). Third, the dose of chromium must be sufficient such that it may be reliably measured above background levels in urine (range of 0.2 to 2 microg/liter) and above the analytical limit of detection (0.2 microg/liter). Fourth, the inter- and intrapersonal variability in background levels of urinary chromium is known to be significant and influenced by food and beverage intake, smoking, and exercise. Thus, the role of each factor must be carefully understood. Finally, it is imperative to have developed a complete understanding of the clinical significance of elevated urinary chromium levels before a study is performed, because higher than background levels, in and of themselves, are not indicative of a significant health concern. The route of exposure, valence of chromium to which people were exposed, exposure time, and duration must all be understood before the biological data can be implemented. We have conducted a total of nine human exposure studies over the past 3 years in an attempt to understand the kinetics of chromium and the impact on urinary, red blood cell (RBC), and plasma biomonitoring programs. The results of these studies are described here and our recommendations are offered for how to design and implement a urinary chromium biomonitoring study. In our view, given some evidence that the dose of hexavalent chromium [Cr(VI)] is sufficient to be measurable above background concentrations of total chromium [Cr(III) and Cr(VI)], duplicated measurements of chromium in plasma and RBCs are, in most cases, a more definitive gauge of environmental exposure than urinary biomonitoring.

Estimation of a chromium inhalation reference concentration using the benchmark dose method: a case study.

The benchmark dose (BD) method has been proposed as an alternative to the NOAEL/UF method for setting reference levels. The BD is the 95% lower confidence limit on a dose corresponding to a 10% increase (or relative change) in an adverse effect. A case study exploring the suitability of the current Cr(III) and Cr(VI) inhalation toxicity data bases to the BD approach is presented. Because chromic acid mists, typical of many occupational Cr(VI) exposures, present a toxicological profile different from that of Cr(VI) particulates, representative of environmental exposures, Cr(VI) particulate data were evaluated separately from Cr(VI) acidic mist data. The current Cr(III) and Cr(VI) acidic mist data bases proved inadequate for BD analysis due to data and/or study quality limitations. Benchmark reference concentrations (RfCs) for particulate Cr(VI) ranging from 0.34 microgram/m3 (for lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF)) to 1.4 micrograms/m3 (for increased lung weights) are derived from data taken from U. Glaser et al. (Arch. Toxicol. 57, 250-256, 1985) and U. Glaser et al. (Environmental Hygiene II, Springer-Verlag, Berlin/New York, 1990). A Cr(VI) particulate RfC of 0.34 microgram/m3 based upon LDH in BALF as the critical effect is proposed. This value may be viewed as conservative since it represents the 95% lower confidence limit on the dose associated with a 10% increase in response for a sensitive endpoint and has appropriate dosimetric adjustments and uncertainty factors incorporated.

An alternative to the USEPA's proposed inhalation reference concentrations for hexavalent and trivalent chromium.

The passage of the Clean Air Act Amendment of 1990 reflects a growing public concern over human exposure to air toxics. The EPA is currently identifying inhalation reference concentrations (RfCs) to be used as risk criteria for determining whether existing or predicted ambient levels of chemicals are above acceptable concentrations. This paper evaluates the risk assessment methods used by the EPA to develop the recently proposed RfC (0.002 micrograms/m3) for both trivalent chromium [Cr(III)] and hexavalent chromium [Cr(VI)]. Based on our evaluation, these RfC values do not appear to have been developed in accordance with standard Agency procedures or classic toxicology methods for setting RfCs. In particular, the "key" study used by the EPA [E. Lindberg and G. Hedenstierna (1983) Arch. Environ. Health 38, 367-374] as the basis for their proposal is not appropriate because it examined only the effects of exposure to chromic acid mist [Cr(VI)], even though most environmental exposure is to Cr(VI) and Cr(III) as a dust. The health hazards of Cr(VI) as an acid mist are significantly different from those associated with Cr(VI) as a dust. Further, the EPA's key study did not evaluate exposure to Cr(III), the toxicity of which is significantly different from both particulate Cr(VI) and chromic acid mist. Finally, the uncertainty factors used to account for data gaps were unusually high, thus providing RfC values equal to or below most naturally occurring environmental levels and standard analytical limits of detection. In this paper, we propose alternative RfCs for Cr(VI) as chromic acid mist and for Cr(VI) as a dust. Based on the Lindberg and Hedenstierna study, we derived an RfC of approximately 0.12 micrograms/m3 for chromic acid mist. An RfC of 1.2 micrograms/m3 is recommended for particulate Cr(VI) based on animal studies that evaluate long-term inhalation exposure to Cr(VI) dust. Due to its low toxicity, an RfC for Cr(III) is not warranted.