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Dermal absorption of pesticides in the rat.

The Office of Pesticide Programs (OPP) of the Environmental Protection Agency has developed a standard protocol for evaluating the dermal penetration of pesticides in the rat. This protocol was formalized in 1994 as a guideline for Dermal Absorption Studies of Pesticides. To date, in excess of 263 studies on the dermal absorption of over 160 pesticide chemicals have been submitted to OPP as part of the pesticide registration and risk assessment processes. The majority of these studies has been performed according to the OPP standard protocol in the rat. These studies constitute the largest database in existence on the dermal absorption of a wide variety of chemicals using a standard protocol. From this standard protocol it is possible to describe, quantitatively with dose and time, the entrance of a chemical into and penetration through the mammalian epidermis into the systemic circulation, its concentration in blood and in the body, and its excretion in urine and feces. This article describes the experimental design of the standard protocol and presents examples of the types of pesticides studied: pesticides that are neither volatile nor damage the skin (the most common type), volatile pesticides, and pesticides that damage the skin. Examples are selected to illustrate differences in the pattern of dermal uptake and subsequent absorption into the systemic compartment among and within the three classes.

Animals↗

Capillary column gas chromatography with nitrogen-phosphorus detection for determination of nitrogen- and phosphorus-containing pesticides in finished drinking waters: collaborative study.

A joint U.S. Environmental Protection Agency/AOAC interlaboratory method validation study was conducted on EPA Method 507, Determination of Nitrogen- and Phosphorus-Containing Pesticides in Finished Drinking Water by Gas Chromatography with a Nitrogen-Phosphorus Detector, to determine the mean recovery and precision for analyses of 45 nitrogen- or phosphorus-containing pesticides in reagent water and finished drinking waters. The study design was based on Youden's nonreplicate plan for collaborative tests of analytical methods. The waters were spiked with 45 nitrogen- or phosphorus-containing pesticides at 6 concentration levels, prepared as 3 Youden pairs. Ten volunteer laboratories extracted the spiked test waters with methylene chloride, performed a solvent exchange with methyl tert-butyl ether, and analyzed an aliquot of each extract by gas chromatography using a nitrogen-phosphorus detector. Results were analyzed using an EPA computer program, which measured recovery and precision for each of the 45 pesticides and compared the performance of the method between water types. Method 507 was judged acceptable for all analytes tested except merphos, which thermally decomposed in the injection port of the gas chromatograph. Five compounds (carboxin, disulfoton, metolachlor, pronamide, and simazine) exhibited statistically significant matrix effects for the finished drinking water. The method has been adopted official first action by AOAC.

Calibration↗

Application of health information to hazardous air pollutants modeled in EPA's Cumulative Exposure Project.

Relatively little is known about the spectrum of health effects, and the scope and level of ambient air concentrations of those pollutants regulated under the Clean Air Act as "hazardous air pollutants". The U.S. Environmental Protection Agency's (USEPA) Cumulative Exposure Project uses currently available emissions inventories, from a variety of source types, and an atmospheric dispersion model to provide estimates of ambient concentrations for 148 hazardous air pollutants (HAPs) in over 60,000 census tracts for the year 1990. This paper uses currently available hazard information for those pollutants and provides a database of potential regulatory threshold concentrations of concern, or "benchmark concentrations," and a methodology for prioritizing and characterizing the quality of the data. In order to demonstrate application of the database and prioritization scheme to outputs from the Cumulative Exposure Project, comparisons were made with the maximum modeled concentration of each individual hazardous air pollutant across the census tracts. Of the 197 benchmark concentrations for cancer and non-cancer (long- and short-term exposures) effects compiled for the study, approximately one half were exceeded with a predominance of exceedance of cancer benchmarks. While the number of benchmark concentrations available to fully characterize potential health effects of these pollutants was limited (approximately 80 percent of HAPs identified as cancer concerns had benchmark concentrations for cancer and 50 percent of all HAPs had non-cancer benchmark concentrations) and there was greater uncertainty in derivation of maximum modeled air concentrations than other levels, the comparison between the two was a useful approach for providing an indication of public health concern from hazardous air pollutants.

Air Pollutants↗

Field demonstration of pervaporation for the separation of volatile organic compounds from a surfactant-based soil remediation fluid.

As part of a Department of Defense project, the US Environmental Protection Agency was responsible for designing, building and field operating a pilot-scale pervaporation unit. The field site was an active dry cleaning facility on the grounds of Marine Corps Base Camp Lejeune in Jacksonville, NC. The overall goal of the project was to remove tetrachloroethylene (PCE) from the soil beneath the dry cleaning shop using a surfactant-based soil remediation fluid and to recycle/reuse the surfactant. In order to reinject the recovered surfactant, the pervaporation unit was required to achieve an average 95% removal of contaminants from the extracted fluid over the duration of the test period. PCE removal averaged 95.8% during peak surfactant levels and exceeded 99.9% in the absence of surfactant, thereby meeting the reinjection requirement. Removal of a group of secondary contaminants at the site, termed Varsol compounds, was monitored via concentrations of three Varsol marker compounds: decane, undecane and 1,3,5-trimethylbenzene. The pervaporation system processed 100,000 gal of groundwater and surfactant solution over a period of 70 days. In order to evaluate and validate process performance, a variety of process variables and properties were monitored over the course of the demonstration. Pervaporation costs are projected to be on the order of $20 per 1000 gal of surfactant solution treated for a moderate size system (10 gpm).

Decontamination↗

The ToxCast program for prioritizing toxicity testing of environmental chemicals.

The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS), and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. This chemical prioritization research program, entitled "ToxCast," is being initiated with the purpose of developing the ability to forecast toxicity based on bioactivity profiling. The proof-of-concept phase of ToxCast will focus upon chemicals with an existing, rich toxicological database in order to provide an interpretive context for the ToxCast data. This set of several hundred reference chemicals will represent numerous structural classes and phenotypic outcomes, including tumorigens, developmental and reproductive toxicants, neurotoxicants, and immunotoxicants. The ToxCast program will evaluate chemical properties and bioactivity profiles across a broad spectrum of data domains: physical-chemical, predicted biological activities based on existing structure-activity models, biochemical properties based on HTS assays, cell-based phenotypic assays, and genomic and metabolomic analyses of cells. These data will be generated through a series of external contracts, along with collaborations across EPA, with the National Toxicology Program, and with the National Institutes of Health Chemical Genomics Center. The resulting multidimensional data set provides an informatics challenge requiring appropriate computational methods for integrating various chemical, biological, and toxicological data into profiles and models predicting toxicity.

Animals↗

Animal carcinogenicity studies: 1. Poor human predictivity.

The regulation of human exposure to potentially carcinogenic chemicals constitutes society's most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or animal data also assessed by the World Health Organisation's International Agency for Research on Cancer (IARC), human carcinogenicity classifications were compatible with EPA classifications only for those 17 having at least limited human data (p = 0.5896). For those 111 primarily reliant on animal data, the EPA was much more likely than the IARC to assign carcinogenicity classifications indicative of greater human risk (p < 0.0001). The IARC is a leading international authority on carcinogenicity assessments, and its significantly different human carcinogenicity classifications of identical chemicals indicate that: 1) in the absence of significant human data, the EPA is over-reliant on animal carcinogenicity data; 2) as a result, the EPA tends to over-predict carcinogenic risk; and 3) the true predictivity for human carcinogenicity of animal data is even poorer than is indicated by EPA figures alone. The EPA policy of erroneously assuming that tumours in animals are indicative of human carcinogenicity is implicated as a primary cause of these errors.

Animals↗

Key issues in the role of peroxisome proliferator-activated receptor agonism and cell signaling in trichloroethylene toxicity.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is thought to be involved in several different diseases, toxic responses, and receptor pathways. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that although PPAR may play a role in liver tumor induction, the role of its activation and the sequence of subsequent events important to tumorigenesis are not well defined, particularly because of uncertainties concerning the extraperoxisomal effects. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we summarize some of the scientific literature published since that time on the effects and actions of PPARalpha that help inform and illustrate the key scientific questions relevant to TCE risk assessment. Recent analyses of the role of PPARalpha in gene expression changes caused by TCE and its metabolites provide only limited data for comparison with other PPARalpha agonists, particularly given the difficulties in interpreting results involving PPARalpha knockout mice. Moreover, the increase in data over the last 5 years from the broader literature on PPARalpha agonists presents a more complex array of extraperoxisomal effects and actions, suggesting the possibility that PPARalpha may be involved in modes of action (MOAs) not only for liver tumors but also for other effects of TCE and its metabolites. In summary, recent studies support the conclusion that determinations of the human relevance and susceptibility to PPARalpha-related MOA(s) of TCE-induced effects cannot rely on inferences regarding peroxisome proliferation per se and require a better understanding of the interplay of extraperoxisomal events after PPARalpha agonism.

Animals↗

Current status of the Gene-Tox Program.

The U.S. Environmental Protection Agency's Gene-Tox Program is a multiphased effort to review and evaluate the existing literature in assay systems available in the field of genetic toxicology. The first phase of the Gene-Tox Program selected assay systems for evaluation, generated expert panel reviews of the data from the scientific literature, and recommended testing protocols for the systems. Phase II established and evaluated the database of chemical genetic toxicity data for its relevance to identifying human health hazards. The ongoing phase III continues reviewing and updating chemical data in selected assay systems. Currently, data exist on over 4000 chemicals in 27 assay systems; two additional assay systems will be included in phase III. The review data are published in the scientific literature and are also publicly available through the National Library of Medicine TOXNET system. The review and analysis components of Gene-Tox comprise 45 published papers, and several others are in preparation. Differences that have been observed between Gene-Tox and National Toxicology Program databases relative to the sensitivity, specificity, accuracy, and predictivity of genetic toxicity data compared to carcinogenesis data are ascribable to differences between the two databases in chemical selection criteria, testing protocols, and chemical class distributions.

Animals↗

Technical basis for EPA's proposed regulation on the cleanup of sites contaminated with radioactivity.

The U.S. Environmental Protection Agency is proposing a regulation for the protection of the public from radioactive contamination at sites that are to be cleaned up and released for public use. The rule will apply to sites under the control of Federal agencies, and will impose limits on radiation doses to individuals living or working on a site following cleanup; it will thereby provide site owners and managers with uniform, consistent cleanup criteria for planning and carrying out remediation. This paper presents an overview of EPA's approach to assessing some of the beneficial and adverse effects associated with various possible values for the annual dose limit. In particular, it discusses the method developed to determine how the choice of cleanup criterion affects (1) the time-integrated potential numbers of non-fatal and fatal radiogenic cancers averted among future populations, (2) the occurrence of radiogenic cancers among remediation workers and the public caused by the cleanup process itself, and (3) the volumes of contaminated soil that may require remediation. The analytic methods described here were used to provide input data and assumptions for the Regulatory Impact Analysis (RIA) that supports the proposed regulation; the RIA also considered non-radiological benefits and costs (i.e., public health, economic, and ecological) of the standards.

Radiation Injuries↗

Methods for detecting long-term CNS dysfunction after prenatal exposure to neurotoxins.

Current U.S. Environmental Protection Agency regulatory guidelines for developmental neurotoxicity emphasize functional categories such as motor activity, auditory startle, and learning and memory. A single test of some simple form of learning and memory is accepted to meet the latter category. The rationale for this emphasis has been that sensitive and reliable methods for assessing complex learning and memory are either not available or are too burdensome, and that insufficient data exist to endorse one approach over another. There has been little discussion of the fact that learning and memory is not a single identifiable functional category and no single test can assess all types of learning and memory. Three methods for assessing complex learning and memory are presented that assess two different types of learning and memory, are relatively efficient to conduct, and are sensitive to several known neurobehavioral teratogens. The tests are a 9-unit multiple-T swimming maze, and the Morris and Barnes mazes. The first of these assesses sequential learning, while the latter two assess spatial learning. A description of each test is provided, along with procedures for their use, and data exemplifying effects obtained using developmental exposure to phenytoin, methamphetamine, and MDMA. It is argued that multiple tests of learning and memory are required to ascertain cognitive deficits; something no single method can accomplish. Methods for acoustic startle are also presented.

Animals↗

Estimates of the health risk reductions associated with attainment of alternative particulate matter standards in two U.S. cities.

As part of its periodic re-evaluation of particulate matter (PM) standards, the U.S. Environmental Protection Agency estimated the health risk reductions associated with attainment of alternative PM standards in two locations in the United States with relatively complete air quality data: Philadelphia and Los Angeles. PM standards at the time of the analysis were defined for particles of aerodynamic diameter less than or equal to 10 microm, denoted as PM-10. The risk analyses estimated the risk reductions that would be associated with changing from attainment of the PM-10 standards then in place to attainment of alternative standards using an indicator measuring fine particles, defined as those particles of aerodynamic diameter less than or equal to 2.5 microm and denoted as PM-2.5. Annual average PM-2.5 standards of 12.5, 15, and 20 microg/m3 were considered in various combinations with daily PM-2.5 standards of 50 and 65 microg/m3. Attainment of a standard or set of standards was simulated by a proportional rollback of "as is" daily PM concentrations to daily PM concentrations that would just meet the standard(s). The predicted reductions in the incidence of health effects varied from zero, for those alternative standards already being met, to substantial reductions of over 88% of all PM-associated incidence (e.g., in mortality associated with long-term exposures in Los Angeles, under attainment of an annual standard of 12.5 microg/m3). Sensitivity analyses and integrated uncertainty analyses assessed the multiple-source uncertainty surrounding estimates of risk reduction.

Air Pollutants↗

Communicating worst-case scenarios: neighbors' views of industrial accident management.

The prospect of industrial accidents motivated the U.S. Congress to require in the Clean Air Act of 1990 that manufacturing facilities develop Risk Management Plans (RMP) to submit to the U.S. Environmental Protection Agency (USEPA) by July 1999. Industry worried that the requirement to communicate to the public a "worst-case scenario" would arouse unnecessary and counterproductive fears among industry neighbors. We report here the results of focus groups and surveys with such neighbors, focusing particularly upon their reactions to messages about a hypothetical worst-case scenario and management of these risks by industry, government, and other parties. Our findings confirmed our hypotheses that citizens would be skeptical of the competence and trustworthiness of these managers and that this stance would color their views of industrial-facility accident risks. People with job ties to industry or who saw industrial benefits to the community as exceeding its risks had more positive views of industrial risks, but still expressed great concern about the risk and doubt about accident management. Notwithstanding these reactions, overall respondents welcomed this and other related information, which they wanted their local industries to supply. Respondents were not more reassured by additional text describing management of accidents by government and industry. However, respondents did react very positively to the concept of community oversight to review plant safety. Claims about the firm's moral obligation or financial self-interest in preventing accidents were also received positively. Further research on innovative communication and management of accident risks is warranted by these results, even before recent terrorist attacks made this topic more salient.

Accidents, Occupational↗

Concentration and detection of cryptosporidium oocysts in surface water samples by method 1622 using ultrafiltration and capsule filtration.

The protozoan parasite Cryptosporidium parvum is known to occur widely in both source and drinking water and has caused waterborne outbreaks of gastroenteritis. To improve monitoring, the U.S. Environmental Protection Agency developed method 1622 for isolation and detection of Cryptosporidium oocysts in water. Method 1622 is performance based and involves filtration, concentration, immunomagnetic separation, fluorescent-antibody staining and 4',6-diamidino-2-phenylindole (DAPI) counterstaining, and microscopic evaluation. The capsule filter system currently recommended for method 1622 was compared to a hollow-fiber ultrafilter system for primary concentration of C. parvum oocysts in seeded reagent water and untreated surface waters. Samples were otherwise processed according to method 1622. Rates of C. parvum oocyst recovery from seeded 10-liter volumes of reagent water in precision and recovery experiments with filter pairs were 42% (standard deviation [SD], 24%) and 46% (SD, 18%) for hollow-fiber ultrafilters and capsule filters, respectively. Mean oocyst recovery rates in experiments testing both filters on seeded surface water samples were 42% (SD, 27%) and 15% (SD, 12%) for hollow-fiber ultrafilters and capsule filters, respectively. Although C. parvum oocysts were recovered from surface waters by using the approved filter of method 1622, the recovery rates were significantly lower and more variable than those from reagent grade water. In contrast, the disposable hollow-fiber ultrafilter system was compatible with subsequent method 1622 processing steps, and it recovered C. parvum oocysts from seeded surface waters with significantly greater efficiency and reliability than the filter suggested for use in the version of method 1622 tested.

Animals↗

Inhalation health risks of manganese: an EPA perspective.

In 1994, the U.S. Environmental Protection Agency (EPA) denied a petition by Ethyl Corporation to allow the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in unleaded gasoline, because of health concerns related to the inhalation of manganese (Mn) particulate emissions from combusted MMT. Although Ethyl successfully challenged EPA's denial of the petition on legal grounds, issues raised in EPA's health risk assessment have not been resolved to date. This paper summarizes features of the EPA health risk characterization, which included the use of various statistical techniques to derive several estimates of inhalation reference concentration (RfC) values for Mn as alternatives to the established value of 0.05 microgram Mn/m3. An exposure assessment projected distributions of personal exposure levels to particulate Mn if MMT were used in all unleaded gasoline. It was estimated that exposure levels of 5-10% of the modeled population might exceed a possible alternative RfC value of 0.1 microgram Mn/m3. However, due to data limitations, the risk characterization for Mn/MMT could raise only qualitative concerns about potential public health impacts and was unable to provide a quantitative estimate of risk. To improve the risk characterization, better information on Mn/MMT population exposures and health effects is needed. Much of this information is expected to be obtained under provisions of Section 211 of the Clean Air Act. Among the specific issues that remain to be resolved are the form or forms of Mn emitted from the combustion of MMT in gasoline and the potentially different toxic properties of Mn in different forms.

Air Pollutants↗

Statistical assessment of violations of water quality standards under Section 303(d) of the clean water act.

Section 303(d) of the Clean Water Act requires states to assess the condition of their waters and to implement plans to improve the quality of waters identified as impaired. U.S. Environmental Protection Agency guidelines require a stream segment to be listed as impaired when greater than 10% of the measurements of water quality conditions exceed numeric criteria. This can be termed a "raw score" assessment approach. Water quality measurements are samples taken from a population of water quality conditions. Concentrations of pollutants vary naturally, measurement errors may be made, and occasional violations of a standard may be tolerable. Therefore, it is reasonable to view the assessment process as a statistical decision problem. Assessment of water quality conditions must be cognizant of the possibility of type I (a false declaration of standards violation) and type II (a false declaration of no violation) errors. The raw score approach is shown to have a high type I error rate. Alternatives to the raw score approach are the Binomial test and the Bayesian Binomial approach. These methods use the same information to make decisions but allow for control of the error rates. The two statistical methods differ based on consideration of prior information about violation. Falsely concluding that a water segment is impaired results in unnecessary planning and pollution control implementation costs. On the other hand, falsely concluding that a segment is not impaired may pose a risk to human health or to the services of the aquatic environment. An approach that recognizes type I and type II error in the water quality assessment process is suggested.

Bayes Theorem↗

Interpretation of male rat renal tubule tumors.

Based on an analysis of recent scientific studies, a Technical Panel of the U.S. Environmental Protection Agency's (EPA) Risk Assessment Forum recently advised EPA risk assessors against using information on certain male rat renal tubule tumors to assess human risk under conditions specified in a new Forum report. Risk assessment approaches generally assume that chemicals producing tumors in laboratory animals are a potential cancer hazard to humans. For most chemicals, including classical rodent kidney carcinogens such as N-ethyl-N-hydroxyethylnitrosamine, this extrapolation remains appropriate. Some chemicals, however, induce accumulation of alpha 2u-globulin (alpha 2u-g), a low molecular weight protein, in the male rat kidney. The alpha 2u-g accumulation initiates a sequence of events that appears to lead to renal tubule tumor formation. Female rats and other laboratory mammals administered the same chemicals do not accumulate low molecular weight protein in the kidney, and they do not develop renal tubule tumors. Because humans appear to be more like other laboratory animals than like the male rat, in this special situation, the male rat is not a good model for assessing human risk. The Forum report stresses the need for full scrutiny of a substantial set of data to determine when it is reasonable to presume that renal tumors in male rats are linked to a process involving alpha 2u-g accumulation and to select appropriate procedures for estimating human risks under such circumstances.

Alpha-Globulins↗

A comparative study of US EPA 1996 and 1999 emission inventories in the west Gulf of Mexico coast region, USA.

Emission inventory is one of the required inputs to air quality models. To assist in the urban and regional modeling efforts, United States Environmental Protection Agency (EPA) has compiled a National Emission Inventory (NEI) for criterion pollutants, and the precursors of ozone and particulate matter (PM). In December 2002, EPA released the 1999 NEI estimates (NEI99), which represent the most recent national emission data. However, the data sets are not in model-ready format for air quality simulations. This present work converts the NEI99 Final Version 2 data sets into Inventory Data Analyzer (IDA) format and processes the data using the Sparse Matrix Operator Kernel Emissions (SMOKE) modeling system to generate a gridded emission inventory in a domain covering the west Gulf Coast Region, USA. The spatial and diurnal emission characteristics of the gridded emission inventories are then assessed and compared with those of the National Emission Trend 1996 (NET96). The NEI99 database contains more complete emission records in both area and point sources. It is also found that NEI99 data exhibit greater emissions with respect to point and mobile sources but smaller emissions with respect to area sources when compared to the corresponding gridded NET96 data in the same study domain. The most distinct differences between the NEI99 and NET96 databases are CO emission of mobile sources, SO2 emissions of point sources, and VOC/PM/NH3/NOx emissions of area and non-road sources. The gridded NEI99 data show low VOC/NOx ratios (<2-5) in the urban areas of the study domain.

Air Pollutants↗

Detection of astroviruses, enteroviruses, and adenovirus types 40 and 41 in surface waters collected and evaluated by the information collection rule and an integrated cell culture-nested PCR procedure.

We evaluated the use of an integrated cell culture-reverse transcription-PCR (ICC-RT-PCR) procedure coupled with nested PCR to detect human astroviruses, enteroviruses, and adenovirus types 40 and 41 in surface water samples that were collected and evaluated by using the Information Collection Rule (ICR) method. The results obtained with the ICC-RT-PCR-nested PCR method were compared to the results obtained with the total culturable virus assay-most-probable-number (TCVA-MPN) method, the method recommended by the U.S. Environmental Protection Agency for monitoring viruses in surface and finished waters. Twenty-nine ICR surface water samples were analyzed. Viruses were concentrated by using filter adsorption-beef extract elution and organic flocculation techniques, and then the preparations were evaluated for viruses by visualizing cytopathic effects in the Buffalo green monkey kidney (BGMK) cell line. In the ICC-RT-PCR-nested PCR technique we used Caco-2 cells to propagate astroviruses and enteroviruses (ICC step), and we used BGMK cells to propagate adenovirus types 40 and 41, as well as enteroviruses. Fifteen of the 29 samples (51.7%) were positive for astrovirus as determined by the ICC-RT-PCR-nested PCR method, and eight of these samples (27.5%) contained infectious astrovirus. Seventeen of the 29 samples (58.6%) were positive for enteroviruses when the BGMK cell line was used, and six (27.6%) of these samples were determined to be infectious. Fourteen of the 29 samples (48.3%) were positive for adenovirus types 40 and 41, and 11 (37.9%) of these samples were determined to be infectious. Twenty-seven of the 29 samples (93.1%) were positive for a virus, and 19 (68.9%) of the samples were positive for an infectious virus. Only 5 of the 29 samples (17.2%) were positive as determined by the TCVA-MPN method. The ICC-RT-PCR-nested PCR method provided increased sensitivity compared to the TCVA-MPN method.

Adenoviruses, Human↗