Human Exposure Scenarios Research Articles

Abstract 3457: Novel polymeric implants for low-dose, continuous exposure to carcinogens

Abstract Current practices to determine the DNA-damaging and carcinogenicity potential of a chemical generally involves treatment of rodents with single or multiple bolus doses. However, humans are almost always exposed to low doses continuously. Thus, carcinogenic potential of a chemical has relied on extrapolation of doses tested in pre-clinical studies. What is needed is a low-dose continuous-exposure system to mimic the human-exposure scenario. We recently described novel polymeric implants capable of providing controlled release of compounds continuously for long duration. When implants of polycaprolactone: F68 (9:1) embedded with benzo[a]pyrene (BP) were grafted subcutaneously in female rats, we found nearly constant levels of DNA adducts over one month period in the liver and lung upon analysis by 32P-postlabeling assay. In this study we describe tissue DNA adduct accumulation over extended periods, and effect of low-dose continuous treatment on cytochrome P450s associated with BP metabolism. Groups of female S/D rats received either no treatment or received subcutaneous sham implants or implants embedded with BP. Animals were euthanized at 1, 2, 4 and 25 weeks and different tissues were collected. Analysis of the liver and lung by 32P-postlabeling showed that the adduct burden in lung (14 - 16 adducts/109 nucleotides) was somewhat higher than in liver (11 - 12 adducts/109 nucleotides) over the 30 day period. At the end of the study, the adduct levels in the liver remained practically at the steady-state (17 adducts/109 nucleotides). However, in the lung, the adduct levels increased by nearly two fold (31 adducts/109 nucleotides). These data suggest that over extended period, the highest adduct accumulation occurred in the lung presumably due to tissue-specific differences in adduct formation and/or removal. To determine if the steady-state adduct levels were related to steady modulation of CYPs, we analyzed CYP1A1 and CYP1B1 at both mRNA and protein levels. It was found that after 1 week of treatment, both CYP1A1 and CYP1B1 were substantially over expressed at both RNA and protein levels and remained up-regulated up to 4 weeks analyzed thus far. The steady-state up-regulation of these CYPs and tissue DNA adduction in this study is consistent with our cigarette smoke exposure study in which female A/J mice showed sustained over expression of CYP1A1 and CYP1B1 during the smoke-exposure period of three months. In summary, the polymeric implants provide a low-dose continuous (“24/7”)-exposure system to determine DNA-damaging and carcinogenicity potential of environmental carcinogens. This sustained-release exposure system is also relevant to the human scenario for determining efficacy of chemopreventive agents. (Supported from CA-118114, CA-125152 and Agnes Brown Duggan Endowment) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3457.

Using urinary solubility data to estimate the level of safety concern of low levels of melamine (MEL) and cyanuric acid (CYA) present simultaneously in infant formulas

Melamine (MEL) and cyanuric acid (CYA) may occur simultaneously in milk products. There is no health based guidance value for the mixture of MEL+CYA. Limited toxicological data indicate that MEL+CYA toxicity occurs at levels lower than the toxic doses of the single compounds. The key adverse effect of MEL+CYA is the formation of crystals in the urinary tract, which is dependent on the solubility of the MEL+CYA complex. Urinary concentrations resulting from oral doses of MEL+CYA and MEL alone have been calculated from published data from animal studies. A human exposure scenario assuming consumption of infant formula contaminated at a level of 1ppm of MEL and CYA each (2ppm of MEL+CYA) was also analyzed. Margins of more than two orders or magnitude were observed between estimated urine concentrations known to be without detectable effects in rats and calculated human urine concentrations. Because the hazard is related to the physico-chemical characteristics of the mixture, there would be a negligible concern associated with crystal formation if the urinary concentration of the complex is within the solubility range. The solubility of MEL+CYA was higher in urine than in water. A strong pH-dependency was observed with the lowest solubility found at pH 5–5.5. The calculated human urinary concentration was about 30 times less than the solubility limit for MEL+CYA in adult human urine. Altogether, these data provide preliminary evidence suggesting that the presence of 1ppm of MEL and CYA each in infant formula is unlikely to be of significant health concern.

Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty.

A recent decline in onset of puberty - especially among girls - has been observed, first in the US in the mid-1990s and now also in Europe. The development of breast tissue in girls occurs at a much younger age and the incidence of precocious puberty (PP) is increasing. Genetic factors and increasing prevalence of adiposity may contribute, but environmental factors are also likely to be involved. In particular, the widespread presence of endocrine-disrupting chemicals (EDCs) is suspected to contribute to the trend of earlier pubertal onset. The factors regulating the physiological onset of normal puberty are poorly understood. This hampers investigation of the possible role of environmental influences. There are many types of EDCs. One chemical may have more than one mode of action and the effects may depend on dose and duration of the exposure, as well as the developmental stage of the exposed individual. There may also be a wide range of genetic susceptibility to EDCs. Human exposure scenarios are complex and our knowledge about effects of mixtures of EDCs is limited. Importantly, the consequences of an exposure may not be apparent at the actual time of exposure, but may manifest later in life. Most known EDCs have oestrogenic and/or anti-androgenic actions and only few have androgenic or anti-oestrogenic effects. Thus, it appears plausible that they interfere with normal onset of puberty. The age at menarche has only declined by a few months whereas the age at breast development has declined by 1 year; thus, the time span from initiation of breast development to menarche has increased. This may indicate an oestrogen-like effect without concomitant central activation of the hypothalamic-pituitary axis. The effects may differ between boys and girls, as there are sex differences in age at onset of puberty, hormonal profiles and prevalence of precocius puberty.

Courage for simplification and imperfection in the 21st century assessment of “Endocrine disruption”

"Endocrine disruption" is a public and political buzzword that has and is still receiving high media attention. Based on the latter, numerous tiered testing strategies have evolved that should ensure that humans will not run a health risk due to the voluntary or involuntary exposure to endocrine active compounds (EAS). An analysis of the currently available knowledge on EAS mediated endocrine disruption in humans demonstrates that there are very few EAS that causally induce endocrine disruptive effects. Conversely, the association EAS exposure with increased risk or incidences of endocrine disruptive effects in humans are difficult to reconcile with the results from animal studies. Consequently, the analysis of the traditional and historically grown tiered approach in EAS testing, often at very high doses or concentrations, demonstrates that the likelihood of detecting EAS with true potential for endocrine disruption in humans is very low, primarily due to inherent differences between the surrogate species and the human, and will provide for a high number of false-positives commensurate with low efficiency, high cost, and often violently disputed interpretations of what the data would mean for human risk assessment. It is thus proposed that EAS testing for putative endocrine disruption in humans and qualitative and quantitative evaluation for risk assessment purposes should be entirely focused on human data, and derived from a combination of in silico and in vitro systems, PBPK modeling, metabonomic or genomic profiling of human tissue, realistic human EAS exposure, dose-effect principles and adverse effect scenarios, human patient or exposure cohort datasets, etc. Animals models should be used only where specific pathways in endocrine physiology and thus development and reproduction is nearly identical to the situation in the human, thereby guaranteeing that causal exposure and effect relationships in the animals can be extrapolated to the human.

Arsenic activates EGFR pathway signaling in the lung.

Arsenic is an established lung carcinogen, however, the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell cycle progression, tumor invasion, and angiogenesis. We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-EGF, and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor, Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95% confidence interval 1.1–15.6) (p = 0.04). These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic-exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.

Trichloroethylene and Ocular Malformations: Analysis of Extant Literature

An evaluation of the scientific literature for trichloroethylene (TCE) identified two reports of ocular defects, specifically microphthalmia/anophthalmia, following prenatal TCE exposure in rats. Herein, these reports are analyzed in detail and interpreted within the context of other developmental TCE exposure studies. The ocular findings following prenatal TCE exposure are reported in studies that were not designed specifically for developmental safety assessment, and thus did not use standard experimental practices. Furthermore, these findings most commonly occurred at TCE doses associated with considerable maternal toxicity. Among the 18 published studies using developmental TCE exposures, only 3 used doses sufficiently high enough to result in maternal toxicity, and of these, only the 2 discussed in detail in this paper demonstrated ocular defects in the offspring. Furthermore, statistically significant effects were only observed at doses that were above the currently accepted guideline limit dose of 1000 mg/kg body weight. All other TCE developmental exposure studies failed to demonstrate ocular defects as a result of prenatal exposure. These results suggest that the micro-/anophthalmia findings were likely a consequence of delivery of an extremely high bolus TCE dose that is irrelevant to human environmental exposure scenarios.

Application of PBPK modeling in support of the derivation of toxicity reference values for 1,1,1-trichloroethane

PBPK modeling has been increasingly applied in chemical risk assessment for dose, route, and species extrapolation. The use of PBPK modeling was explored in deriving toxicity reference values for 1,1,1-trichloroethane (1,1,1-TCE). This effort involved a 5-step process: (i) reconstruction of several published PBPK models for 1,1,1-TCE in the rat and human; (ii) selection of appropriate pharmacokinetic datasets for model comparison; (iii) determination of the most suitable PBPK model for supporting reference value derivation; (iv) PBPK model simulation of two critical studies to estimate internal dose metrics; and (v) calculation of internal dose metrics for human exposure scenarios for reference value derivation. The published model by Reitz et al. [Reitz, R.H., McDougal, J.N., Himmelstein, M.W., Nolan, R.J., Schumann, A.M., 1988. Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations. Toxicol. Appl. Pharmacol. 95, 185–199] was judged the most suitable. This model has liver, fat, and rapidly and slowly perfused compartments, contains a saturable process for 1,1,1-TCE hepatic metabolism, and accommodates multiple exposure pathways in three species. Data from a human volunteer study involving acute inhalation exposure [Mackay, C.J., Campbell, L., Samuel, A.M., Alderman, K.J., Idzikowski, C., Wilson, H.K., Gompertz, D., 1987. Behavioral changes during exposure to 1,1,1-trichloroethane: time-course and relationship to blood solvent levels. Am. J. Ind. Med. 11, 223–239] and a chronic rat inhalation study [Quast, J.F., Calhoun, L.L., Frauson, L.E., 1988. 1,1,1-Trichloroethane formulation: a chronic inhalation toxicity and oncogenicity study in Fischer 344 rats and B6C3F1 mice. Fundam. Appl. Toxicol. 11, 611–625] were selected to simulate appropriate internal dosimetry data from which to derive reference value points of departure. Duration, route, and species extrapolations were performed based on internal dose metrics.

Contamination, risk, and heterogeneity: on the effectiveness of aquifer remediation

The effectiveness of aquifer remediation is typically expressed in terms of a reduction in contaminant concentrations relative to a regulated maximum contaminant level (MCL), and is usually confirmed by sparse monitoring data and/or simple model calculations. Here, the effectiveness of remediation is re-examined from a more thorough risk-based perspective that goes beyond the traditional MCL concept. A methodology is employed to evaluate the health risk to individuals exposed to contaminated household water that is produced from groundwater. This approach explicitly accounts for differences in risk arising from variability in individual physiology and water use, the uncertainty in estimating chemical carcinogenesis for different individuals, and the uncertainties and variability in contaminant concentrations within groundwater as affected by transport through heterogeneous geologic media. A hypothetical contamination scenario is developed as a case study in a saturated, alluvial aquifer underlying an actual Superfund site. A baseline (unremediated) human exposure and health risk scenario, as induced by contaminated groundwater pumped from this site, is predicted and compared with a similar estimate based upon pump-and-treat exposure intervention. The predicted reduction in risk in the remediation scenario is not an equitable one—that is, it is not uniform to all individuals within a population and varies according to the level of uncertainty in prediction. The importance of understanding the detailed hydrogeologic connections that are established in the heterogeneous geologic regime between the contaminated source, municipal receptors, and remediation wells, and its relationship to this uncertainty is demonstrated. Using two alternative pumping rates, we develop cost-benefit curves based upon reduced exposure and risk to different individuals within the population, under the presence of uncertainty.

Kinetics of Sarin (GB) Following a Single Sublethal Inhalation Exposure in the Guinea Pig

To improve toxicity estimates from sublethal exposures to chemical warfare nerve agents (CWNA), it is necessary to generate mathematical models of the absorption, distribution, and elimination of nerve agents. However, current models are based on representative data sets generated with different routes of exposure and in different species and are designed to interpolate between limited laboratory data sets to predict a wide range of possible human exposure scenarios. This study was performed to integrate CWNA sublethal toxicity data in male Duncan Hartley guinea pigs. Specific goal was to compare uptake and clearance kinetics of different sublethal doses of sarin (either 0.1 × or 0.4 × LC50) in blood and tissues of guinea pigs exposed to agent by acute whole-body inhalation exposure after the 60-min LC50 was determined. Arterial catheterization allowed repeated blood sampling from the same animal at various time periods. Blood and tissue levels of acetylcholinesterase, butyrylcholinesterase, and regenerated sarin (rGB) were determined at various time points during and following sarin exposure. The following pharmacokinetic parameters were calculated from the graph of plasma or RBC rGB concentration versus time: time to reach the maximal concentration; maximal concentration; mean residence time; clearance; volume of distribution at steady state; terminal elimination-phase rate constant; and area under plasma concentration time curve extrapolated to infinity using the WinNonlin analysis program 5.0. Plasma and RBC t1/2 for rGB was also calculated. Data will be used to develop mathematical model of absorption and distribution of sublethal sarin doses into susceptible tissues.

Approaches to the risk assessment of genotoxic carcinogens in food: A critical appraisal

The present paper examines the particular difficulties presented by low levels of food-borne DNA-reactive genotoxic carcinogens, some of which may be difficult to eliminate completely from the diet, and proposes a structured approach for the evaluation of such compounds. While the ALARA approach is widely applicable to all substances in food that are both carcinogenic and genotoxic, it does not take carcinogenic potency into account and, therefore, does not permit prioritisation based on potential risk or concern. In the absence of carcinogenicity dose–response data, an assessment based on comparison with an appropriate threshold of toxicological concern may be possible. When carcinogenicity data from animal bioassays are available, a useful analysis is achieved by the calculation of margins of exposure (MOEs), which can be used to compare animal potency data with human exposure scenarios. Two reference points on the dose–response relationship that can be used for MOE calculation were examined; the T25 value, which is derived from linear extrapolation, and the BMDL10, which is derived from mathematical modelling of the dose–response data. The above approaches were applied to selected food-borne genotoxic carcinogens. The proposed approach is applicable to all substances in food that are DNA-reactive genotoxic carcinogens and enables the formulation of appropriate semi-quantitative advice to risk managers.

Agricultural Chemical Safety Assessment: A Multisector Approach to the Modernization of Human Safety Requirements

Better understanding of toxicological mechanisms, enhanced testing capabilities, and demands for more sophisticated data for safety and health risk assessment have generated international interest in improving the current testing paradigm for agricultural chemicals. To address this need, the ILSI Health and Environmental Sciences Institute convened a large and diverse group of international experts to develop a credible and viable testing approach that includes scientifically appropriate studies that are necessary without being redundant, and that emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Benefits of the proposed approach include improved data for risk assessment, greater efficiency, use of fewer animals, and better use of resources. From the outset of this endeavor, it was unanimously agreed that a tiered approach should be designed to incorporate existing knowledge on the chemistry, toxicology, and actual human exposure scenarios of the compound, with integration of studies on metabolism/kinetics, life stages, and systemic toxicities. Three international task forces were charged with designing study types and endpoints on metabolism/ kinetics, life stages, and systemic toxicities to be used in the tiered approach. This tiered testing proposal departs from the current standardized list of hazard studies used by many national authorities, and represents the first comprehensive effort of its kind to scientifically redesign the testing framework for agricultural chemicals.

Dosimetric Adjustments for Interspecies Extrapolation of Inhaled Poorly Soluble Particles (PSP)

Direct calculation of delivered dose in the species of interest potentially affects the magnitude of an uncertainty factor needed to address extrapolation of laboratory animal data to equivalent human exposure scenarios, thereby improving the accuracy of human health risk estimates. Development of an inhalation reference concentration (RfC) typically involves extrapolation of an effect level observed in a laboratory animal exposure study to a level of exposure in humans that is not expected to result in an appreciable health risk. The default dose metric used for respiratory effects is the average deposited dose normalized by regional surface area. However, the most relevant dose metric is generally one that is most closely associated with the mode of action leading to the response. Critical factors in determining the best dose metric to characterize the dose-response relationship include the following: the nature of the biological response being examined; the magnitude, duration, and frequency of the intended exposure scenario; and the mechanisms by which the toxicants exert their effects.Dosimetry models provide mechanistic descriptions of these critical factors and can compute species-specific dose metrics. In this article, various dose metrics are postulated based on potential modes of action for poorly soluble particles (PSP). Dosimetry models are used to extrapolate the internal dose metric across species and to estimate the human equivalent concentration (HEC). Dosimetry models for the lower respiratory tract (LRT) of humans and rats are used to calculate deposition and retention using the principle of particle mass balance in the lower respiratory tract. Realistic asymmetric lung geometries using detailed morphometric measurements of the tracheobronchial (TB) airways in rats and humans are employed in model calculations. Various dose metrics are considered for the TB and pulmonary (P) regions. Because time is an explicit parameter incorporated in species-specific constants such as mucociliary clearance rates used in the models, the impact of the application of optimal model structures to refine adjustments and assumptions used in default risk assessment approaches to address exposure duration are discussed.HEC estimates were found for particles ranging in sizes that corresponded to existing toxicity studies of PSP (0.3 to 5μm). A dose metric expressed as number of particles per biologically motivated normalization factors (e.g., number of ventilatory units, number of alveoli, and number of macrophages) was lower than the current default of mass normalized to regional surface area for either deposited or retained dose estimates. Retained dose estimates were lower than deposited dose estimates across all particle sizes evaluated. Dose metrics based on the deposited mass per unit area in small and large airways of the TB region indicate HECs of 1 to 5 times those of rats: that is, an equivalent exposure to humans which would achieve the same internal dose as in the rat would be 1 to 5 times greater. HEC estimates in the TB region increase with an increase in particle size for particles from 0.3 to ≤ 2μm, then decrease with an increase in particle size for particles >2 μm in the small airways and >3 μm in the large airways. The HEC decreases with increase in particle size in the P region across all particle sizes studied, and the decrease has a more significant slope for those particles >2 μm due to the limited inhalability of particles this size in rats relative to humans.Our modeling results elucidate a number of important issues to be considered in assessing current default approaches to dosimetry adjustment for inhaled PSP. Simulation of realistic, polydisperse particle distributions for the human exposure scenario results in reduced HEC estimates compared to estimates derived with the experimental particle distribution used in the laboratory animal study. Consideration should be given also to replacing the default dose metric of normalized deposited dose in the P region with normalized retained dose. Chronic effects are more likely due to retained dose and estimates calculated using retained versus deposited mass are shown to be lower across all particle sizes. Because dose metrics based on normalized particle number rather than normalized mass result in lower HEC estimates, use of inhaled mass as the default should also be revisited, if the pathogenesis suggests particle number determines the mode of action. Based on demonstrated age differences, future work should pursue the construction of “lifetime” estimates calculated by sequentially appending simulations for each specific age span.

The impact of long-term mercury contamination on the new human exposure scenarios in the North Region of Mato Grosso, Amazon basin

The present study addresses the long-term mercury contamination as consequence of the goldmining activities taking into account the fish Hg levels and fish consumption in different areas in the north region of the Mato Grosso State. The study involves the environmental characterization of the region. and the fish-farming areas. Geographic Information has been emphased on the cultural and social habits by a specific questionnaire. A monitoring mercury program was carried out. taking different fish species from contaminated and background areas. The results show that in Alta Floresta. Hg level of the piscivorous fish are decreasing in comparison with the previous exposure scenario The present exposure scenario ranges from 0.09 to 3.9 μg/kg/d. The highest exposure dose was detected in the rural area of Patanaita and the lowest in Nova Monte Verde. The results of this study support governmental decision-makers and local community s representatives to deliberate conservative measures to protect human health.

Risk-Based Zoning Strategy for Soil Remediation at an Industrial Site

After determining at an early stage of the project that the future land use of this New Jersey chemical manufacturing site remain industrial in nature, the site was zoned according to risk. The chemicals of concern (COCs) at the site included relatively low levels of mono- and polynuclear aromatic hydrocarbons, chlorinated aliphatics, as well as other volatile and semivolatile compounds. Direct human exposure scenarios were the key to the mitigation of risks related to soils because the groundwater migration pathway was already interrupted using groundwater recovery. A focused remedial strategy was developed to ensure that the exposure pathways (inhalation, ingestion, and dermal contact) are alleviated and the remedial measures are protective to the workers operating and/or maintaining the site. The risk evaluation process included a preliminary risk assessment (Tier 1) based on a comparison with pertinent soil cleanup criteria, a prioritization analysis to rank zones, chemicals and pathways of concern, and an application of the Risk Based Corrective Action (RBCA) approach (Tier 2) for construction worker exposure scenario. The risk assessment identified selected areas that would benefit from remedial actions. Prioritization Analysis classified the site into five high-priority (comprising 97% of the total health-based risk), three medium-priority (contributing to remaining 2 to 3% of the risk), and adequately protected areas. The boundaries and volumes of affected areas were delineated based on confirmatory soil sampling and statistical analyses. The remedial technologies selected for the site have achieved appropriate reduction in risk to comply with all State regulations and include (in addition to the institutional controls):• Capping the site where only immobilesemivolatile contaminants are present• Excavation and on-site treatment of the soils impacted by volatile organic com pounds through ex situ low temperature desorption, or alternative “biopile” treatment and natural attenuation, and• Excavation and off-site disposal of limited volumes of soilsThis risk-based, integral approach helped identify the real significance of contamination present at the site and facilitated the development of suitable and adequate remedies. Had not it been for this approach, the mere comparison with soil cleanup criteria would have unnecessarily resulted in denoting all areas as nuisance contributors, and thus requiring some actions. New Jersey Department of Environmental Protection (NJDEP) has approved this approach and contributed to its accomplishment.

Understanding and Managing Indoor Air Exposure Assessments at RCRA Sites

The 2000 RCRA National Conference was conducted August 15-17, 2000, in Washington, D.C., to allow state and federal authorities to review regulatory issues associated with the Resource Conservation and Recovery Act (RCRA) program. One of the RCRA reform issues discussed at the conference included the Government Performance and Results Act (GPRA) Environmental Indicators (EI). EIs have been designed to provide clarity in cleanup objectives and spur progress towards meeting the U.S. Environmental Protection Agency's (USEPA's) national RCRA cleanup goals. This article focuses on the human exposure indicator and, more specifically, on indoor air exposures and how to assess whether such exposure is actually occurring. While indoor air exposure can be a critical component of the human exposure scenarios, realistic predictions of the exposures are difficult to produce. This article provides an overview of the regulatory issues related to the indoor air exposure pathway. It also discusses the use of modeling in criteria development and risk evaluation and presents a case study of how the USEPA wants the modeling to occur, and an opinion of where this RCRA reform issue is heading and how to evaluate indoor air exposures.

Institutional Control: Impacts on Human Health Risk Assessment Exposure Scenario Development

Abstract The concept of institutional control has been present in the environmental industry since the advent of the Comprehensive Environmental Response, Compensation and Liability Act of 1976. Many federal facilities undergoing environmental remediation under this Act have made valuable use of institutional control as an interim remedial action and as an important portion of final remedial alternatives. The core concept of institutional control has been to put in place administrative policies or physical barriers between potentially exposed populations and a contaminant source to avoid unwanted exposures to the potentially exposed populations. The concept of estimating the risk to humans from exposure to contamination and its use as a defining criteria as to whether a site must undergo active remediation have been around just as long. Institutional control and human health risk assessment are intimately linked as crucial parts of the greater remedial alternative analysis topic—human health risk assessment being a determining criteria for proceeding with active remediation and institutional control being one of those remedial alternatives. Institutional control’s core concept has very dramatic influences on the science and practice of human health risk assessment. A vital portion of human health risk assessment involves defining probable human receptor populations by using a set of criteria of which land use scenarios are a key part. A foundational goal of human health risk assessment has been to define realistic land use scenarios that can limit the number and types of potential exposed populations for which risk estimates must be calculated. Institutional control by its regulatory definition limits potential land use on a given contaminated site, therefore limiting the realm of potential (realistic) exposed populations that should be considered in a human health risk assessment. This relationship makes the early identification of institutional control as part of an overall final remedy paramount to conducting efficient realistic human health risk assessment. In successfully doing so, remedial action managers and risk assessors must confide closely in each other to determine the probability of institutional control as a viable remedial action. Such cooperative strategy saves resources for both the remedial action manager and the risk assessor by avoiding unnecessary work to account for improbable exposure scenarios that can drive unnecessary remediation. The early consideration of institutional controls in defining future land use scenarios and therefore risk assessment exposure scenarios saves considerable money, time, and resources involved in successful remediation projects.

Causes, costs, and estimates of rabies postexposure prophylaxis treatments in the United States.

The incidence of rabies in humans in the United States is low. However, contacts with potentially rabid animals result in thousands of human rabies postexposure prophylaxis treatments (PEPs) each year. PEP is expensive, not without risk of adverse reactions, and in many instances unnecessary. Increased reports of cases of rabies in animals (4,880 cases in 1990, 9,495 in 1993, and 7,124 in 1996) suggested that PEPs could be increasing. Application of 1981 PEP incidence rates gave an estimate of approximately 16,000 PEPs during 1996, while calculations based on annual sales of a rabies biological during 1996 gave an estimate of approximately 39,000 PEPs. Appropriate usage of PEP requires careful evaluation of human exposure scenarios and adherence to approved guidelines.

A physiologically-based pharmacokinetic model assessment of methyl t-butyl ether in groundwater for a bathing and showering determination.

Methyl t-butyl ether (MTBE) is a gasoline additive that has appeared in private wells as a result of leaking underground storage tanks. Neurological symptoms (headache, dizziness) have been reported from household use of MTBE-affected water, consistent with animal studies showing acute CNS depression from MTBE exposure. The current research evaluates acute CNS effects during bathing/showering by application of physiologically-based pharmacokinetic (PBPK) techniques to compare internal doses in animal toxicity studies to human exposure scenarios. An additional reference point was the delivered dose associated with the acute Minimum Risk Level (MRL) for MTBE established by the Agency for Toxic Substances and Disease Registry. A PBPK model for MTBE and its principal metabolite, t-butyl alcohol (TBA) was developed and validated against published data in rats and humans. PBPK analysis of animal studies showed that acute CNS toxicity after MTBE exposure can be attributed principally to the parent compound since the metabolite (TBA) internal dose was below that needed for CNS effects. The PBPK model was combined with an exposure model for bathing and showering which integrates inhalation and dermal exposures. This modeling indicated that bathing or showering in water containing MTBE at 1 mg/L would produce brain concentrations approximately 1000-fold below the animal effects level and twofold below brain concentrations associated with the acute MRL. These findings indicate that MTBE water concentrations of 1 mg/L or below are unlikely to trigger acute CNS effects during bathing and showering. However, MTBE's strong odor may be a secondary but deciding factor regarding the suitability of such water for domestic uses.

The oral administration of Polysorbate 80 to the immature female rat does not increase uterine weight

Some xenobiotics display estrogenic activity in in vitro and/or in vivo systems. Previous studies by Gajdova et al. have shown that polysorbate 80 (also known as Tween 80) administered by intraperitoneal injection to neonatal female rats on days 4–7 after birth produced estrogenic effects including earlier vaginal opening, prolongation of the estrus cycle and persistent vaginal estrus [1]. Some of these effects were evident many weeks after cessation of administration of polysorbate 80. The present study has evaluated the estrogenic properties of polysorbate 80 following oral administration, a route of exposure which is more relevant for the consideration of human health hazard. The effects of polysorbate 80 at oral gavage doses of up to 5 g/kg/day for 3 consecutive days on uterine growth of immature female rats, a commonly used in vivo mammalian assay for estrogenic activity, have been determined. Estradiol benzoate administered subcutaneously was used as a positive control and significantly increased uterine weight in this age and strain of female rat (21–23 days, Alpk:APfSD Wistar derived) by up to 4.5-fold above vehicle control values. Polysorbate 80 administered orally to rats had no effect on uterine weight. Thus, intrinsic estrogenic effects of polysorbate 80 reported following its intraperitoneal injection to neonatal 4-day-old female rats are not manifest when it is administered by oral gavage to immature 20- to 22-day-old female rats. This latter route of exposure is of more relevance to human exposure scenarios and these data are, therefore, important in assessing hazard/risk of polysorbate 80 to man.

Advances in EPA's Indirect Exposure Modeling Methodology

ABSTRACTThe Environmental Protection Agency's National Center for Environmental Assessment is currently revising and updating its approach to modeling the health risks from indirect exposure to combustor emissions. The updated method is intended to provide the necessary tools for estimating these health risks and to provide the necessary algorithms for the calculation of contaminant concentrations in water bodies, soil, and the terrestrial and aquatic food chains resulting from the deposition and transfer of atmospheric pollutants. Significant additions to the approach include the expansion of the application of exposure methods at a site, the description of procedures for defining the study population at a site, and ways to develop distributions of individual risk for members of the study population. This paper focuses on the changes in the human exposure scenarios of the updated method and presents an overview of the development of an exposure scenario.