Peer review of a cancer weight of evidence assessment based on updated toxicokinetics, genotoxicity, and carcinogenicity data for 1,3-dichloropropene using a blinded, virtual panel of experts.

A cancer weight of evidence (WOE) analysis based on updated toxicokinetics, genotoxicity, and carcinogenicity data for 1,3-dichloropropene was peer reviewed by a panel of experts. Historically, 1,3-dichloropropene has been classified in the U.S. as "likely to be carcinogenic to humans" via oral and inhalation exposure routes based upon the results of rodent cancer bioassays conducted in the 1980s. Contemporary studies led the authors of the WOE analysis to conclude that the currently manufactured form of 1,3-dichloropropene is not mutagenic and not carcinogenic below certain doses, pointing to a threshold-based approach for cancer risk assessment. SciPinion conducted a peer review of the WOE analysis using methods for assembling and managing blinded expert panels that maximize expertise while minimizing potential selection/participation bias. The process was implemented through a web-based application that poses a series of questions soliciting the experts' scientific opinions and observations about specific topics. The goal of the peer review was to have experts provide conclusions about the WOE for carcinogenicity classification of 1,3-dichloropropene, identify potential data gaps, and evaluate the validity of a threshold-based risk assessment for 1,3-dichloropropene. Based on a robust peer review of the current scientific information, a cancer WOE classification of "not likely to be carcinogenic to humans" is best supported for 1,3-dichloropropene. This conclusion is reached with a high degree of consensus (consensus score = 0.92) across expert panel members.

Risk assessment and Biomonitoring Equivalent for 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) and tetrabromobenzoic acid (TBBA).

2-ethylhexyl-2,3,4,5 tetrabromobenzoate (TBB) is used as a flame retardant. Biomonitoring for TBB exposures include the metabolite, tetrabromobenzoic acid (TBBA), in urine. We derived a Reference Dose (RfD) for TBB and a Biomonitoring Equivalent (BE) for TBBA in urine. Three longer-term studies of oral gavage dosing of a commercial mixture BZ-54 (which includes 70% TBB) in rats were evaluated for deriving the RfD. The 95% lower confidence limits on the BMD associated with a 1 SD change from the mean (BDMLSD) values ranged from 77 to 134 mg/kg-day. The mean BMDLSD value of 91 mg/kg-day for maternal body weight changes was selected as the appropriate point of departure (POD), corresponding to a human equivalent dose (PODHEC) of 25 mg/kg-day. A total composite uncertainty factor (UF) of 300 yields an RfD of 0.08 mg/kg-day. A urinary mass excretion fraction (Fue) of 0.6 for TBBA following oral doses of TBB in rats was used to calculate BEs for TBBA in urine of 2.5 mg/L and 2.5 mg/g cr. Mean (5.3 × 10-6 mg/L) and maximum (340 × 10-6 mg/L) levels of TBBA measured in urine from human volunteers reported in the literature indicates margins of safety (MOS) are approximately 450,000 and 7,000, respectively.

Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential.

Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.S. FDA led us to assess the potential for developmental toxicity under relevant product-use scenarios. Estimates from a physiologically based pharmacokinetic modeling approach suggest that occupational use of alcohol-based topical antiseptics in the healthcare industry can generate low, detectable concentrations of ethanol in blood. This unintended systemic dose probably reflects contributions from both dermal absorption and inhalation of volatilized product. The resulting internal dose is low, even under hypothetical, worst case intensive use assumptions. A significant margin of exposure (MOE) exists compared to demonstrated effect levels for developmental toxicity under worst case use scenarios, and the MOE is even more significant for typical anticipated occupational use patterns. The estimated internal doses of ethanol from topical application of alcohol-based hand sanitizers are also in the range of those associated with consumption of non-alcoholic beverages (i.e., non-alcoholic beer, flavored water, and orange juice), which are considered safe for consumers. Additionally, the estimated internal doses associated with expected exposure scenarios are below or in the range of the expected internal doses associated with the current occupational exposure limit for ethanol set by the Occupational Safety and Health Administration. These results support the conclusion that there is no significant risk of developmental or reproductive toxicity from repeated occupational exposures and high frequency use of ABHSs or surgical scrubs. Overall, the data support the conclusion that alcohol-based hand sanitizer products are safe for their intended use in hand hygiene as a critical infection prevention strategy in healthcare settings.

Assessment of the mode of action underlying development of rodent small intestinal tumors following oral exposure to hexavalent chromium and relevance to humans.

Abstract Chronic exposure to high concentrations of hexavalent chromium (Cr(VI)) in drinking water causes intestinal adenomas and carcinomas in mice, but not in rats. Cr(VI) causes damage to intestinal villi and crypt hyperplasia in mice after only one week of exposure. After two years of exposure, intestinal damage and crypt hyperplasia are evident in mice (but not rats), as are intestinal tumors. Although Cr(VI) has genotoxic properties, these findings suggest that intestinal tumors in mice arise as a result of chronic mucosal injury. To better understand the mode of action (MOA) of Cr(VI) in the intestine, a 90-day drinking water study was conducted to collect histological, biochemical, toxicogenomic and pharmacokinetic data in intestinal tissues. Using MOA analyses and human relevance frameworks proposed by national and international regulatory agencies, the weight of evidence supports a cytotoxic MOA with the following key events: (a) absorption of Cr(VI) from the intestinal lumen, (b) toxicity to intestinal villi, (c) crypt regenerative hyperplasia and (d) clonal expansion of mutations within the crypt stem cells, resulting in late onset tumorigenesis. This article summarizes the data supporting each key event in the MOA, as well as data that argue against a mutagenic MOA for Cr(VI)-induced intestinal tumors.

Evaluation of biomonitoring data from the CDC National Exposure Report in a risk assessment context: perspectives across chemicals.

BACKGROUND: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment-based values now allow interpretation of these biomonitoring data in a public health risk context. OBJECTIVES: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER. METHODS: We identified available risk assessment-based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates. CONCLUSIONS: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10-4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.

Assessment of margin of exposure based on biomarkers in blood: an exploratory analysis.

In chemical risk assessment, exposures in humans are often compared to no-observed-adverse-effect levels or benchmark doses for sensitive adverse responses ("points of departure") in laboratory species to assess whether a sufficient "margin of exposure" (MOE) is attained to ensure safety. Conventionally, the default target MOE based on external dose is drawn from uncertainty factors of 10 each for inter- and intra-species extrapolation. The increasing availability of blood-based biomonitoring data in humans as well as measured and modeled blood concentrations in laboratory animals in key studies underlying chemical risk assessments may allow assessments of MOE to be made by comparing blood concentrations of parent compound in humans compared to those in the laboratory species at the point of departure for the risk assessment. This exploratory analysis provides an initial evaluation of whether the default MOE of 100 typically applied on an external dose basis is protective when applied on the basis of comparison of blood concentrations between laboratory animals and humans. The evaluation is conducted using a generic physiologically-based pharmacokinetic model of the structure typically applied to volatile organic compounds. Additional considerations relative to other classes of compounds are also addressed. Based on this evaluation, for chemicals with characteristics consistent with the modeling conducted here under certain conditions, the default MOE of 100 is more protective when applied to comparative blood concentrations than when applied on an external dose basis. Depending upon the chemical characteristics, the toxicokinetic components of the inter- and/or intra-species uncertainty factor could be reduced or eliminated when inter- and intra-species comparisons and extrapolations are made based on blood concentrations of parent compound of interest.

1,3-Butadiene: I. Review of metabolism and the implications to human health risk assessment.

1,3-Butadiene (BD) is a multisite carcinogen in laboratory rodents following lifetime exposure, with mice demonstrating greater sensitivity than rats. In epidemiology studies of men in the styrene-butadiene rubber industry, leukemia mortality is associated with butadiene exposure, and this association is most pronounced for high-intensity BD exposures. Metabolism is an important determinant of BD carcinogenicity. BD is metabolized to several electrophilic intermediates, including epoxybutene (EB), diepoxybutane (DEB), and epoxybutane diol (EBD), which differ considerably in their genotoxic potency (DEB >> EB > EBD). Important species differences exist with respect to the formation of reactive metabolites and their subsequent detoxification, which underlie observed species differences in sensitivity to the carcinogenic effects of BD. The modes of action for human leukemia and for the observed solid tumors in rodents are both likely related to the genotoxic potencies for one or more of these metabolites. A number of factors related to metabolism can also contribute to nonlinearity in the dose-response relationship, including enzyme induction and inhibition, depletion of tissue glutathione, and saturation of oxidative metabolism. A quantitative risk assessment of BD needs to reflect these species differences and sources of nonlinearity if it is to reflect the current understanding of the disposition of BD.

Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective.

The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advisory Board recommendations of using the most recent data and giving consideration to peak exposures to BD have been followed. If cumulative BD ppm-years is to be used as the predictor of the leukemia rate ratio, then the performance of that predictor is statistically significantly improved if the slope in the predictor is estimated with age and the cumulative number of BD peaks (where a BD peak is any exposure, regardless of duration, to a BD concentration above 100 ppm) added as categorical covariates. After age and the cumulative number of BD peaks are incorporated as categorical covariates in the Poisson regression model, the estimated concentration (EC(001)) corresponding to an excess risk of 0.001 as a result of continuous environmental exposure is 11.2 ppm; however, the estimated slope for BD cumulative ppm-years in the linear rate ratio for leukemia used to derive this EC(001) is not statistically significantly different from zero. Sensitivity analyses using alternative models indicate either essentially no risk or estimated EC(001) values of 9 and 77 ppm. Analyses suggesting the absence of a statistically significant low-dose risk versus cumulative BD ppm-years are presented. Sensitivity analyses of other malignant neoplasms of lymphatic and hematopoietic tissue (specifically, lymphoid and myeloid neoplasms) resulted in conclusions about the dose-response modeling methodology that were supportive of the methodology used for leukemia.