RESUMO
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).
Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Poluentes do Solo , Disponibilidade Biológica , Argila , Monitoramento Ambiental , Humanos , Hidrocarbonetos Policíclicos Aromáticos/análise , Medição de Risco , Solo , Poluentes do Solo/análiseRESUMO
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.
Assuntos
Argila/química , Hidrocarbonetos Policíclicos Aromáticos/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Poluentes do Solo/farmacocinética , Solo/química , Administração Oral , Disponibilidade Biológica , Humanos , Hidrocarbonetos Policíclicos Aromáticos/administração & dosagem , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Medição de Risco , Poluentes do Solo/administração & dosagem , Poluentes do Solo/efeitos adversos , Propriedades de SuperfícieRESUMO
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).
Assuntos
Etanolaminas/administração & dosagem , Etanolaminas/química , Animais , Etanolaminas/efeitos adversos , Feminino , Humanos , Hiperplasia/induzido quimicamente , Inflamação/induzido quimicamente , Inalação/efeitos dos fármacos , Doenças da Laringe/induzido quimicamente , Masculino , Metaplasia/induzido quimicamente , RatosRESUMO
This paper highlights the pervasive misconception concerning 1994 findings from Hatch et al. about ozone (O3) tissue dose in humans versus rats. That study exposed humans to 0.4 ppm and rats to 2 ppm 18O-labeled O3 and found comparable incorporation of 18O into bronchoalveolar lavage constituents. However, during O3 exposure humans were exercising, which increased their ventilation rate five-fold, while rats were at rest. This resulted in similar O3 tissue doses between the two species, and predominantly explained the comparable 18O incorporation at five-fold different concentrations. The five-times higher exercising human inhalation rate offset the five-times lower concentration, producing the same human dose expected at rest at 2 ppm (i.e. 0.4 ppm × 4686 L/2 hour ≈ 2 ppm × 998 L/2 hour). In 2013, Hatch et al. showed that resting humans and resting rats experienced fairly comparable 18O incorporation at the same O3 exposure concentration and activity state into BALF cells. Despite these findings, we show here that in the peer-reviewed literature a substantial proportion of researchers continue to perpetuate the misunderstanding that human lung tissue doses of O3 are simply 3-5 times greater than rat doses at the same O3 concentration, due to interspecies differences, and not considering activity state. It is important to correct this misconception to ensure an appropriate understanding of the implications of O3 studies by the scientific community and policy experts making regulatory decisions (e.g. the US Environmental Protection Agency's National Ambient Air Quality Standards for O3).
Assuntos
Poluentes Atmosféricos , Pulmão/metabolismo , Ozônio/administração & dosagem , Animais , Humanos , Ratos , Especificidade da EspécieRESUMO
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.
Assuntos
Poluentes Atmosféricos/toxicidade , Butadienos/toxicidade , Carcinogênese/induzido quimicamente , Carcinógenos/toxicidade , Hemiterpenos/toxicidade , Exposição por Inalação/efeitos adversos , Modelos Teóricos , Neoplasias/induzido quimicamente , Pentanos/toxicidade , Poluentes Atmosféricos/sangue , Poluentes Atmosféricos/farmacocinética , Animais , Área Sob a Curva , Butadienos/sangue , Butadienos/farmacocinética , Testes de Carcinogenicidade , Carcinógenos/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento Ambiental/métodos , Feminino , Hemiterpenos/sangue , Hemiterpenos/farmacocinética , Humanos , Modelos Lineares , Masculino , Camundongos , Pentanos/sangue , Pentanos/farmacocinética , Ratos Endogâmicos F344 , Medição de Risco , Fatores de Risco , Especificidade da Espécie , Texas , Fatores de Tempo , IncertezaRESUMO
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).
Assuntos
Cromo/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Poluentes Ocupacionais do Ar/toxicidade , Animais , Indústria Química , Cromatos/química , Cromatos/toxicidade , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Neoplasias Pulmonares/epidemiologia , Masculino , Doenças Profissionais/etiologia , Distribuição de Poisson , Modelos de Riscos Proporcionais , Análise de Regressão , Risco , Medição de Risco/métodos , Fatores de RiscoRESUMO
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.
Assuntos
Carcinógenos Ambientais/toxicidade , Cromo/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Animais , Carcinógenos Ambientais/administração & dosagem , Cromo/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Exposição por Inalação , Valores de Referência , Medição de Risco/métodosRESUMO
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.
Assuntos
Poluentes Atmosféricos/toxicidade , Carcinógenos/toxicidade , Exposição Ambiental/efeitos adversos , Neoplasias Pulmonares/induzido quimicamente , Níquel/toxicidade , Animais , Humanos , Neoplasias Pulmonares/epidemiologia , Medição de Risco , IncertezaRESUMO
A chronic noncancer toxicity assessment for 1,3-butadiene (BD) has been conducted by the Texas Commission on Environmental Quality (TCEQ) using information not available to the U.S. Environmental Protection Agency (U.S. EPA) in 2002. The TCEQ developed a chronic reference value (ReV) of 33 microg/m3 (15 ppb). The chronic ReV is based on the same animal study and critical endpoint used by U.S. EPA for ovarian atrophy in B6C3F1 mice, but uses mode of action (MOA) information that indicates the diepoxide metabolite is responsible for ovarian atrophy. In addition, diepoxide-specific hemoglobin adduct data in mice, rats, and humans and other experimental data that became available after 2002 were used to support a conservative data-derived toxicokinetic animal-to-human uncertainty factor (UFA) of 0.3. The default toxicodynamic UFA of 3 was used, together with the data-derived toxicokinetic UFA of 0.3, resulting in a total UFA of 1. The necessary experimental data were not available to calculate a chemical-specific adjustment factor, although supporting data suggest the toxicokinetic UFA may range from 0.01 to 0.2. The chronic ReV value, along with a unit risk factor developed by the TCEQ, will be used to evaluate ambient air monitoring data so that the general public is protected against adverse health effects from chronic exposure to BD.
Assuntos
Butadienos/efeitos adversos , Animais , Atrofia/induzido quimicamente , Butadienos/metabolismo , Relação Dose-Resposta a Droga , Exposição Ambiental/normas , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Ovário/efeitos dos fármacos , Ovário/patologia , Gravidez , Ratos , Valores de ReferênciaRESUMO
The Texas Commission on Environmental Quality (TCEQ) has developed an inhalation unit risk factor (URF) for 1,3-butadiene based on leukemia mortality in an updated epidemiological study on styrene-butadiene rubber production workers conducted by researchers at the University of Alabama at Birmingham. Exposure estimates were updated and an exposure estimate validation study as well as dose-response modeling were conducted by these researchers. This information was not available to the U.S. Environmental Protection Agency when it prepared its health assessment of 1,3-butadiene in 2002. An extensive analysis conducted by TCEQ discusses dose-response modeling, estimating risk for the general population from occupational workers, estimating risk for potentially sensitive subpopulations, effect of occupational exposure estimation error, and use of mortality rates to predict incidence. The URF is 5.0 x 10(-7) per microg/m(3) or 1.1 x 10(-6) per ppb and is based on a Cox regression dose-response model using restricted continuous data with age as a covariate, and a linear low-dose extrapolation default approach using the 95% lower confidence limit as the point of departure. Age-dependent adjustment factors were applied to account for possible increased susceptibility for early life exposure. The air concentration at 1 in 100,000 excess leukemia mortality, the no-significant-risk level, is 20 microg/m(3) (9.1 ppb), which is slightly lower than the TCEQ chronic reference value of 33 microg/m(3) (15 ppb) protective of ovarian atrophy. These values will be used to evaluate ambient air monitoring data so the general public is protected against adverse health effects from chronic exposure to 1,3-butadiene.