Oral and Dermal Bioavailability Studies of Polycyclic Aromatic Hydrocarbons from Soils Containing Weathered Fragments of Clay Shooting Targets.

The relative oral bioavailability and dermal absorption of chemical substances from environmental media are key factors that are needed to accurately estimate site-specific risks and manage human exposures. This study evaluated the in vivo relative oral bioavailability and in vitro dermal absorption of several polycyclic aromatic hydrocarbons (PAHs) found in soils collected from two formerly used Department of Defense sites impacted by weathered fragments of clay shooting targets. Concentrations of individual carcinogenic PAHs in the ≤250 µm fraction of soil ranged from approximately 0.1 to 100 mg/kg. A novel sample preparation method was developed to produce accurate and precise test diets for oral studies. The resulting test diets showed consistent concentrations of PAHs in soil- and soil-extract-amended diets and a consistent PAH concentration profile. Mean oral relative bioavailability factors (RBAFs) and dermal absorption fractions (ABSd) for benzo(a)pyrene ranged from 8 to 14% and 0.58 to 1.3%, respectively. Using the RBAF and ABSd values, measured here, for benzo(a)pyrene in USEPA's regional screening level equations yields concentrations for residential soils that are approximately eight times higher than those when default values are used (e.g., 9.6 vs 1.2 mg/kg at a target excess risk of 1 × 10-5).

Risk assessment implications of site-specific oral relative bioavailability factors and dermal absorption fractions for polycyclic aromatic hydrocarbons in surface soils impacted by clay skeet target fragments.

Risk assessment conclusions for a site may differ when using site-specific versus default values for the relative bioavailability factor (RBAF) and dermal absorption fraction (ABS.d), because these inputs affect both surface soil screening levels and risk/hazard estimates. Indeed, our case study demonstrates that different conclusions may be reached as to regulatory need for remedial action to protect human health when evaluating soil sampling data for seven carcinogenic polycyclic aromatic hydrocarbons (PAHs) using site-specific versus default TCEQ and USEPA residential soil screening levels. Use of site-specific RBAF and ABS.d values increased carcinogenicity-based TCEQ and USEPA surface soil screening levels for PAHs by 4.4- and 6-fold on average, respectively. Soil screening levels for PAHs were more sensitive to changes in ingestion exposure route parameters than to changes in dermal exposure route parameters. Accordingly, site-specific RBAF and ABS.d information has important implications for screening chemicals at PAH-impacted sites, and in addition provides more realistic estimates of risks/hazards posed by PAHs in soil with reduced uncertainty compared to estimates based on default RBAF and ABS.d values. Although default values are generally deemed acceptable by regulatory agencies, use of risk/hazard estimates based on these default values may compel insufficiently justified remedial action in some instances.

Development of an inhalation reference concentration for diethanolamine.

An inhalation reference concentration (RfC) was developed for diethanolamine (DEA), based principally on evaluation of three animal studies (Gamer et al., 1993, 1996, 2008). The RfC (25 µg/m3) was based on statistically significantly increased relative liver weight in female rats in Gamer et al. (2008) as the critical effect. The lower confidence limit on the benchmark dose (BMDL10 of 5.5 mg/m3) was adjusted to a human equivalent concentration and to continuous exposure before dividing the final point of departure (2.3 mg/m3) by a total factor of 90 that considered standard key areas of uncertainty (intrahuman variability, potential interspecies toxicodynamic differences, database limitations). While laryngeal effects observed in Gamer et al. (2008) were also considered as candidate critical effects, evaluation of the adversity and human relevance of rat laryngeal squamous metaplasia and concomitant effects at the various exposure levels resulted in identifying a LOAEL for laryngeal squamous hyperplasia and chronic inflammation that was much higher than the liver weight LOAEL identified. The RfC of 25 µg/m3 is considered health protective for the general population and can be used to evaluate the potential health effects of long-term environmental exposure of the general public (i.e., long-term, ambient air dispersion modelling or monitoring data).

Development of an inhalation unit risk factor for isoprene.

A unit risk factor (URF) was developed for isoprene based on evaluation of three animal studies with adequate data to perform dose-response modeling (NTP, 1994, 1999; Placke et al., 1996). Ultimately, the URF of 6.2E-08 per ppb (2.2E-08 per µg/m(3)) was based on the 95% lower confidence limit on the effective concentration corresponding to 10% extra risk for liver carcinoma in male B6C3F1 mice after incorporating appropriate adjustment factors for species differences in target tissue metabolite concentrations and inhalation dosimetry. The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 160 ppb (450 µg/m(3)). This concentration is almost 4400 times lower than the lowest exposure level associated with statistically increased liver carcinoma in B6C3F1 mice in the key study (700 ppm in Placke et al., 1996) and is above typical isoprene breath concentrations reported in the scientific literature. Continuous lifetime environmental exposure to the 1 in 100,000 excess risk level of 160 ppb would be expected to raise the human blood isoprene area under the curve (AUC) less than one-third of the standard deviation of the endogenous mean blood AUC. The mean for ambient air monitoring sites in Texas (2005-2014) is approximately 0.13 ppb.

Development of an inhalation unit risk factor for hexavalent chromium.

A unit risk factor (URF) was developed for hexavalent chromium (CrVI). The URF is based on excess lung cancer mortality in two key epidemiological studies of chromate production workers. The Crump et al. (2003) study concerns the Painesville, OH worker cohort, while Gibb et al. (2000) regards the Baltimore, MD cohort. A supporting assessment was also performed for a cohort from four low-dose chromate plants (Leverkusen and Uerdingen, Germany, Corpus Christi, TX, Castle Hayne, NC). For the Crump et al. (2003) study, grouped observed and expected number of lung cancer mortalities along with cumulative CrVI exposures were used to obtain the maximum likelihood estimate and asymptotic variance of the slope (ß) for the linear multiplicative relative risk model using Poisson regression modeling. For the Gibb et al. (2000) study, Cox proportional hazards modeling was performed with optimal exposure lag and adjusting for the effect of covariates (e.g., smoking) to estimate ß values. Life-table analyses were used to develop URFs for each of the two key studies, as well as for supporting and related studies. The two key study URFs were combined using weighting factors relevant to confidence to derive the final URF for CrVI of 2.3E-03 per µgCrVI/m(3).

Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment.

The carcinogenicity of hexavalent chromium(CrVI) is of significant interest to regulatory agencies for the protection of public health and to industry. Additionally, the mode of action (MOA) and conditions under which CrVI may induce carcinogenicity (e.g., reductive capacity considerations) have recently been the subject of significant scientific debate. Epidemiological data supported by data relevant to the carcinogenic MOA support considering nonlinear-threshold carcinogenic assessments for comparison to default linear low-dose extrapolation approaches. This study reviews epidemiological studies available in the scientific literature and conducts additional statistical dose-response analyses to identify potential carcinogenic thresholds and points of departure (PODs) in the context of supportive MOA information for a nonlinear-threshold inhalation carcinogenic assessment. Dosimetric adjustments and application of appropriate uncertainty factors (total UF of 30) to the selected cumulative exposure POD results in a cancer-based chronic inhalation reference value (ReV) of 0.24 µgCrVI/m(3). This chronic ReV is 300 times higher than the 1 in 100,000 excess cancer risk air concentration of 8E-04 µg/m(3) based on USEPA's unit risk factor.

Development of a unit risk factor for nickel and inorganic nickel compounds based on an updated carcinogenic toxicity assessment.

The TCEQ has developed a URF for nickel based on excess lung cancer in two epidemiological studies of nickel refinery workers with nickel species exposure profiles most similar to emissions expected in Texas (i.e., low in sulfidic nickel). One of the studies (Enterline and Marsh, 1982) was used in the 1986 USEPA assessment, while the other (Grimsrud et al., 2003) is an update to an earlier study (Magnus et al., 1982) used by USEPA. The linear multiplicative relative risk model with Poisson regression modeling was used to obtain maximum likelihood estimates and asymptotic variances for cancer potency factors (ß) using cumulative nickel exposure levels versus observed and expected lung cancer mortality (Enterline and Marsh, 1982) or lung cancer incidence cases (Grimsrud et al., 2003). Life-table analyses were then used to develop URFs from these two studies, which were combined using weighting factors relevant to confidence to derive the final URF for nickel of 1.7E-04 per µg/m³. The de minimis air concentration corresponding to a 1 in 100,000 extra lung cancer risk level is 0.059 µg/m³. The TCEQ will use this conservative value to protect the general public in Texas against the potential carcinogenic effects from chronic exposure to nickel.