Abstract  This document presents the scope of the risk evaluation to be conducted for 1-BP. If a hazard, exposure, condition of use or potentially exposed or susceptible subpopulation has not been discussed, EPA, at this point in time, is not intending to include it in the scope of the risk evaluation. As per the rulemaking, Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control Act (TSCA), with respect to conditions of use in conducting a risk evaluation under TSCA, EPA will first identify “circumstances” that constitute “conditions of use” for each chemical. While EPA interprets this as largely a factual determination—i.e., EPA is to determine whether a chemical substance is actually involved in one or more of the activities listed in the definition—the determination will inevitably involve the exercise of some discretion.

Abstract  As a replacement for chlorofluorocarbons that cause ozone depletion, 1-bromopropane has been widely used in work place. In the present study, the formation of N-7-guanine adduct in DNA by 1-bromopropane was evaluated in vitro to elucidate the possible mechanism of its toxic action. N-7-Propyl guanine was chemically synthesized and structurally characterized by NMR, UV, HPLC, and liquid chromatographyelectrospray ionization mass spectrometry (LC- ESI MS) for using as a reference standard. An incubation of 2'-deoxyguanosine with 1-bromopropane produced N-7-propyl adduct, which was identified by UV, HPLC and ESI-MS. In addition, N-7-guanine adduct was also identified from the incorporation of calf thymus DNA with 1-bromopropane at the physiological condition by LC-ESI MS. Furthermore, the production of adduct was proportional to the amounts of 1-bromopropane used. These results indicated that the molecular mechanism underlying toxic effects of 1-bromopropane would be associated with the adduct formation on DNA at least in part.

Abstract  This review provides variability statistics for polymorphic enzymes that are involved in the metabolism of xenobiotics. Six enzymes were evaluated: cytochrome P-450 (CYP) 2D6, CYP2E1, aldehyde dehydrogenase-2 (ALDH2), paraoxonase (PON1), glutathione transferases (GSTM1, GSTT1, and GSTP1), and N-acetyltransferases (NAT1 and NAT2). The polymorphisms were characterized with respect to (1) number and type of variants, (2) effects of polymorphisms on enzyme function, and (3) frequency of genotypes within specified human populations. This information was incorporated into Monte Carlo simulations to predict the population distribution and describe interindividual variability in enzyme activity. The results were assessed in terms of (1) role of these enzymes in toxicant activation and clearance, (2) molecular epidemiology evidence of health risk, and (3) comparing enzyme variability to that commonly assumed for pharmacokinetics. Overall, the Monte Carlo simulations indicated a large degree of interindividual variability in enzyme function, in some cases characterized by multimodal distributions. This study illustrates that polymorphic metabolizing systems are potentially important sources of pharmacokinetic variability, but there are a number of other factors including blood flow to liver and compensating pathways for clearance that affect how a specific polymorphism will alter internal dose and toxicity. This is best evaluated with the aid of physiologically based pharmacokinetic (PBPK) modeling. The population distribution of enzyme activity presented in this series of articles serves as inputs to such PBPK modeling analyses.

Abstract  Biological monitoring has become one of the methods to measure exposure, with the advantage that it gives information about the concentration of a substance that actually enters the body and reflects the inter-individual differences in uptake and metabolic variation. However, limited information is available on inter- and intra-individual variability of biomarkers. The aim of this study was to gather information about the biological component of inter-individual variation in biomarkers using results from volunteer studies. Open literature and other (internal) sources were searched to find human volunteer studies utilizing biological monitoring. Ultimately 41 studies were included in our analysis, with a total of 6747 observations for one or more biomarkers from 223 volunteers. The data from these studies were grouped on the basis of study, substance under investigation, exposure route, biological matrix, exposure duration, dose and number of exposure events to obtain 278 homogeneous groups (strata) for statistical analysis. Variability was assessed in two ways. Firstly, estimates of biomarker half-life were calculated for each individual, thereby allowing the estimation of inter-individual variability in half-lives within the homogeneous groups. Secondly, variation in biomarker concentrations at a given time point was estimated. For estimated half-lives the GSDs ranged from 1.0 to 6.8. The variability in estimated half-lives did not differ much for the different types of substances. For concentrations at a given time point the average GSDs within strata ranged from 1.0 to 5.6. Again, variability did not differ much for different groups (e.g., type of substance). The median variability component was 0.11 (range 0-3.0). In conclusion, volunteer studies enable the estimation of both variation in half-lives and variation in biomarker levels in the well-defined homogeneous groups. Comparison of our results with other studies indicates that variation due to biological differences within and between people is quite substantial in homogeneous exposure groups. The relative contribution of this biological component to the total variation will be smaller when variance components are estimated in less homogeneous groups, such as those in occupational and environmental settings. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Abstract  Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes that metabolizes ethanol to acetaldehyde, and is induced by recent ethanol ingestion. There is evidence that interindividual variability in the expression and functional activity of this cytochrome (CYP) may be considerable. Genetic polymorphisms in CYP2E1 were identified and linked to altered susceptibility to hepatic cirrhosis induced by ethanol and esophageal and other cancers in some epidemiological studies. Therefore, it is important to evaluate how such polymorphisms affect CYP2E1 function and whether it is possible to construct a population distribution of CYP2E1 activity based upon the known effects of these polymorphisms and their frequency in the population. This analysis is part of the genetic polymorphism database project described in the lead article in this series and followed the approach described in that article (Ginsberg et al., 2009, this issue). Review of the literature found that there are a variety of CYP2E1 variant alleles but the functional significance of these variants is still unclear. Some, but not all, studies suggest that several upstream 5' flanking mutations affect gene expression and response to inducers such as ethanol or obesity. None of the coding-region variants consistently affects enzyme function. Part of the reason for conflicting evidence regarding genotype effect on phenotype may be due to the wide variety of exposures such as ethanol or dietary factors and physiological factors including body weight or diabetes that modulate CYP2E1 expression. In conclusion, evidence is too limited to support the development of a population distribution of CYP2E1 enzyme activity based upon genotypes. Health risk assessments may best rely upon data reporting interindividual variability in CYP2E1 function for input into physiologically based pharmacokinetic (PBPK) models involving CYP2E1 substrates.

Abstract  A 28-day repeated dose inhalation study was conducted in Sprague Dawley rats. Nominal air concentrations were 0, 2 mg/1, 5 mg/1 and 8 mg/1. All dose groups showed decreased weight gains compared to controL Mortality was seen in the high dose group: 8 of 10 males and 3 of 10 females died or were sacrificed before the end of the studies. High dose animals surviving to the end of the study were considered manal Target organ effects identified by histopathology in the high dose group included of facts on the nasal passages, cystitis and dilated bladder, and vacuotation of grey and white matter of the nervous system. Occasional lesions included increased or decreased ben..sopoietic activity of the bone marrow, hypo- or lack of spermatogenesis, pyometra, and vaginitis.