Abstract  Dialkyl phthalates are plasticizers used in household products made from polyvinyl chloride (PVC). Diisononyl phthalate (DINP) is the principal phthalate in soft plastic toys. Because DINP is not tightly bound to PVC, it may be released when children mouth PVC products. The potential chronic health risks of phthalate exposure to infants have been under scrutiny by regulatory agencies in Europe, Canada, Japan, and the U.S. This report describes a risk assessment of DINP exposure from children's products, by the U.S. Consumer Product Safety Commission (CPSC) staff. This report includes the findings of a CPSC Chronic Hazard Advisory Panel (CHAP) which: (1) concluded that DINP is unlikely to present a human cancer hazard and (2) recommended an acceptable daily intake (ADI) level of 120 microg/kg-d, based on spongiosis hepatis in rats. The risk assessment incorporates new measurements of DINP migration rates from 24 toys and a new observational study of children's mouthing activities, with a detailed characterization of the objects mouthed. Probabilistic methods were used to estimate exposure. Mouthing behavior and, thus, exposure depend on the child's age. Approximately 42% of tested soft plastic toys contained DINP. Estimated DINP exposures for soft plastic toys were greatest among children 12-23 months old. The mean exposure for this age group was 0.08 (95% confidence interval 0.04-0.14) microg/kg-d, with a 99th percentile of 2.4 (1.3-3.2) microg/kg-d. The authors conclude that oral exposure to DINP from mouthing soft plastic toys is not likely to present a health hazard to children. The opinions expressed by the authors have not been reviewed or approved by, and do not necessarily reflect the views of, the U.S. Consumer Product Safety Commission. Because this material was prepared by the authors in their official capacity, it is in the public domain and may be freely copied or reprinted.

Abstract  Background: Maternal risk factors have been tabulated for women of childbearing age using defined age ranges. However, statistics for factors strongly related to age may be overly influenced by values for the youngest and oldest women in a range, because pregnancies are most likely for ages 20-35. Objective: This report evaluates adjustment methods, based on the probability of pregnancy, for calculating estimates of risk factors for women of childbearing age. Methods: Adjusted and unadjusted estimates for environmental and nutritional variables were calculated from the 1999-2008 National Health and Nutrition Examination Survey (NHANES) for women aged 16-49. U.S. births were used to determine the probability of pregnancy. Results: Adjusted and unadjusted estimates differed for some, but not all, examined variables. More marked differences were observed for the environmental variables compared with the nutritional variables. Adjusted estimates were within about 5% of the unadjusted estimates for the nutritional variables. Adjusted geometric means for lead and mercury were about 7%-10% lower, and for polychlorinated biphenyl (or PCB) about 25% lower, than their respective unadjusted geometric means. With few exceptions, different adjustment methods led to similar estimates. Conclusion: When calculating statistics for women of childbearing age, the decision to adjust for age or not to adjust appears to be more important than the choice of adjustment method. Although the results suggest only small differences among adjustment methods, approaches based on the NHANES design and sample weighting methodology may be the most robust for other applications.

Abstract  The Guidelines for Exposure Assessment describe the general concepts of exposure assessment including definitions and associated units, and by providing guidance on the planning and conducting of an exposure assessment. Guidance is also provided on presenting the results of the exposure assessment and characterizing uncertainty. Although these Guidelines focus on exposures of humans to chemical substances, much of the guidance also pertains to assessing wildlife exposure to chemicals, or human exposures to biological, noise, or radiological agents. The Guidelines include a glossary which helps standardize terminology used by the Agency in exposure assessment. They emphasize that exposure assessments done as part of a risk assessment need to consider the hazard identification and dose-response parts of the risk assessment in the planning stages of the exposure assessment so that these three parts can be smoothly integrated into the risk characterization. The Guidelines discuss and reference a number of approaches and tools for exposure assessment, along with discussion of their appropriate use. The Guidelines also stress that exposure estimates along with supporting information will be fully presented in Agency risk assessment documents, and that Agency scientists will identify the strengths and weaknesses of each assessment by describing uncertainties, assumptions, and limitations, as well as the scientific basis and rationale for each assessment.

Abstract  Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n = 20; steatosis, n = 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n = 10; and NASH (no longer fatty), n = 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p = 0.001) and CYP2C19 (p = 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p = 0.001) and CYP2C9 (diclofenac, p = 0.0001; tolbutamide, p = 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor α and interleukin 1β was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1α expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.