Abstract  Human hepatic CYP2E1 expression developmental changes likely have an impact on the effects of xenobiotics metabolized by the encoded enzyme. To resolve previous conflicting results, CYP2E1 content was determined in human hepatic microsomes from samples spanning fetal (n = 73, 8-37 weeks) and postnatal (n = 165, 1 day-18 years) ages. Measurable immunodetectable CYP2E1 was seen in 18 of 49 second-trimester (93-186 gestational days) and 12 of 15 third-trimester (>186 days) fetal samples (medians = 0.35 and 6.7 pmol/mg microsomal protein, respectively). CYP2E1 in neonatal samples was low and less than that of infants 31 to 90 days of age, which was less than that of older infants, children, and young adults [median (range) = 8.8 (0-70); 23.8 (10-43); 41.4 (18-95) pmol/mg microsomal protein, respectively; each P < 0.001, analysis of variance, post hoc]. Among those older than 90 days of age, CYP2E1 content was similar. A 4-fold or greater intersubject variation was observed among samples from each age group, with the greatest variation, 80-fold, seen among neonatal samples. Among subjects of known gestational and postnatal age (n = 29) increasing protein content was associated with increasing postnatal age (P < 0.001, linear regression), but only equivocally with increasing gestational age (P = 0.07). Individuals from the third trimester through 90 days postnatal age with one or more CYP2E1*1D alleles had lower CYP2E1 protein content than similar-aged subjects who were homozygous CYP2E1*1C. In summary, CYP2E1 was clearly expressed in human fetal liver. Furthermore, the postnatal data suggest that infants less than 90 days old would have decreased clearance of CYP2E1 substrates compared with older infants, children, and adults.

Abstract  The mission of National Center for Environmental Assessment (NCEA) of EPA's Office of Research and Development is to provide guidance and risk assessments aimed at protecting human health and the environment. To accomplish this mission, NCEA works to develop and improve the models, databases, tools, assumptions, and extrapolations used in risk assessments. This handbook is a tool developed by NCEA aimed at refining the assumptions used in exposure assessments and reducing uncertainty. This handbook was first published in 1989 and later updated in 1997 to provide statistical data on the various human factors used in assessing exposure. This revised edition of the handbook provides the most up-to-date data on these exposure factors. The recommended values are based solely on our interpretations of the available data. In many situations different values may be appropriate to use in consideration of policy, precedent or other factors. The Exposure Factors Handbook provides a summary of the available statistical data on various factors used in assessing human exposure. This Handbook is addressed to exposure assessors inside the Agency as well as outside, who need to obtain data on standard factors to calculate human exposure to environmental agents. These factors include: drinking water consumption, soil ingestion, inhalation rates, dermal factors including skin area and soil adherence factors, consumption of fruits and vegetables, fish, meats, dairy products, homegrown foods, human milk intake, human activity factors, consumer product use, and building characteristics. Recommended values are for the general population and also for various segments of the population who may have characteristics different from the general population. NCEA has strived to include full discussions of the issues that assessors should consider in deciding how to use these data and recommendations.

Abstract  Evaluation of environmental risks posed by potentially hazardous substances requires achieving a balance between over- and underprotection. i.e., between societal benefits posed by the use of particular substances and their potential risks. Uncertainty (e.g., only laboratory data may be available, field or epidemiological data may be limited and less than clear-cut, etc.) will always exist and is often conservatively dealt with by the use of so-called "safety" or "uncertainty" factors, some of which remain relatively little changed since their origin in 1945. Extrapolations involving safety factors for both aquatic and terrestrial environments include inter-and intraspecies, acute-to-chronic, lowest-to no-observed-effect concentration (NOEC), and laboratory-to-held extrapolation (e.g., extrapolation of laboratory results to the field). To be realistic, such extrapolations need to have a clear relationship with the field effect of concern and to be based on good science. The end result is, in any case, simply an estimate of a field NOEC, not an actual NOEC. Science-based versus policy-driven safety factors, including their uses and limitations, are critically examined in the context of national and international legislation on risk assessment. Key recommendations include providing safety factors as a potential threshold effects range instead of a discrete number and using experimental results rather than defaulting to safety factors to compensate for lack of information. This latter recommendation has the additional value of rendering safety factors predictive rather than simply protective. We also consider the so-called "Precautionary Principle," which originated in 1980 and effectively addresses risk by proposing that the safety factor should be infinitely large.

Abstract  EU chemicals legislation requires the use of all available information for hazard and risk assessment before new tests on vertebrates are proposed or conducted. In this context, extrapolation approaches for avoiding chronic fish testing on the basis of existing data have been explored. Simple linear relationships and interspecies sensitivity ratios between Daphnia and fish were calculated and acute-to-chronic relationships and ratios were calculated for fish, taking into consideration the mode of action. The best fitted relationships for the prediction of chronic fish toxicity are obtained based on acute fish and Daphnia data. Chemicals acting by unspecific reactivity and non-polar narcosis give the strongest acute and chronic Daphnia-to-chronic fish relationship. With acute fish data, strong relationships are obtained for all mode of action. Daphnia was found to be more sensitive than fish to several aniline derivatives and pesticides acting through cholinesterase inhibition, and less sensitive than fish to known endocrine disruptors. Extreme (i.e. <1 or >100) interspecies sensitivity ratios were mainly evident for chemicals acting by polar narcosis and specific reactivity. The safety factor of 100 commonly applied in environmental risk assessment does not seem to be equally protective for each mode of action.

Abstract  Lithium-ion battery technology is projected to be the leapfrog technology for the electrification of the drive-train and to provide stationary storage solutions to enable the effective use of renewable energy sources. The technology is already in use for low-power applications such as consumer electronics and power tools. Extensive research and development has enhanced the technology to a stage where it seems very likely that safe and reliable lithium-ion batteries will soon be on board hybrid electric and electric vehicles and connected to solar cells and windmills. However; the safety of the technology is still a concern, service life is not Yet sufficient, and costs are too high. This paper summarizes the state of the art of lithium-ion battery technology for none nonexperts. It lists materials and processing for batteries and summarizes the costs associated with them. This paper should foster an overall understanding of materials and processing and the need to overcome the remaining barriers for a successful market introduction.

Abstract  Dose-response analysis of binary developmental data (e.g., implant loss, fetal abnormalities) is best done using individual fetus data (identified to litter) or litter-specific statistics such as number of offspring per litter and proportion abnormal. However, such data are not often available to risk assessors. Scientific articles usually present only dose-group summaries for the number or average proportion abnormal and the total number of fetuses. Without litter-specific data, it is not possible to estimate variances correctly (often characterized as a problem of overdispersion, intralitter correlation, or “litter effect”). However, it is possible to use group summary data when the design effect has been estimated for each dose group. Previous studies have demonstrated useful dose-response and trend test analyses based on design effect estimates using litter-specific data from the same study. This simplifies the analysis but does not help when litter-specific data are unavailable. In the present study, we show that summary data on fetal malformations can be adjusted satisfactorily using estimates of the design effect based on historical data. When adjusted data are then analyzed with models designed for binomial responses, the resulting benchmark doses are similar to those obtained from analyzing litter-level data with nested dichotomous models.

Abstract  This risk evaluation for n-methylpyrrolidone (NMP) was performed in accordance with the Frank R. Lautenberg Chemical Safety for the 21st Century Act and is being issued following public comment and peer review. The Frank R. Lautenberg Chemical Safety for the 21st Century Act amended the Toxic Substances Control Act (TSCA), the Nation’s primary chemicals management law, in June 2016. Under the amended statute, EPA is required, under TSCA Section 6(b), to conduct risk evaluations to determine whether a chemical substance presents unreasonable risk of injury to health or the environment, under the conditions of use, without consideration of costs or other non-risk factors, including an unreasonable risk to potentially exposed or susceptible subpopulations, identified as relevant to the risk evaluation. Also, as required by TSCA Section (6)(b), EPA established, by rule, a process to conduct these risk evaluations, Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control Act (82 FR 33726) (Risk Evaluation Rule). This risk evaluation is in conformance with TSCA Section 6(b), and the Risk Evaluation Rule, and is to be used to inform risk management decisions. In accordance with TSCA Section 6(b), if EPA finds unreasonable risk from a chemical substance under its conditions of use in any final risk evaluation, the Agency will propose actions to address those risks within the timeframe required by TSCA. However, any proposed or final determination that a chemical substance presents unreasonable risk under TSCA Section 6(b) is not the same as a finding that a chemical substance is “imminently hazardous” under TSCA Section 7. The conclusions, findings, and determinations in this final risk evaluation are for the purpose of identifying whether the chemical substance presents unreasonable risk or no unreasonable risk under the conditions of use, in accordance with TSCA Section 6, and are not intended to represent any findings under TSCA Section 7.