Robert Benson

Hazard to the developing male reproductive system from cumulative exposure to phthalate esters--dibutyl phthalate, diisobutyl phthalate, butylbenzyl phthalate, diethylhexyl phthalate, dipentyl phthalate, and diisononyl phthalate.

Phthalate esters are found in a wide variety of consumer and food packing products. Hence there is widespread exposure of the human population to these chemicals. Some of the phthalate esters are known to be toxic to the developing male reproductive system. This paper derives a reference dose (RfD) for each of the phthalate esters (dibutyl phthalate, diisobutyl phthalate, butylbenzyl phthalate, diethylhexyl phthalate, dipentyl phthalate, and diisononyl phthalate) that cause these effects. As these phthalate esters cause similar adverse biological effects and have the same mechanism of action, it is appropriate in a risk assessment to consider the potential adverse effects from cumulative exposure to these chemicals using a dose addition model. This paper provides examples of a cumulative risk assessment using the hazard index and relative potency approaches from the RfDs derived from studies in laboratory animals and exposure information in people. The results of the cumulative risk assessments for both a US and a German population show that the hazard index is below one. Thus it is unlikely that humans are suffering adverse developmental effects from current environmental exposure to these phthalate esters.

Nationwide reconnaissance of contaminants of emerging concern in source and treated drinking waters of the United States

When chemical or microbial contaminants are assessed for potential effect or possible regulation in ambient and drinking waters, a critical first step is determining if the contaminants occur and if they are at concentrations that may cause human or ecological health concerns. To this end, source and treated drinking water samples from29 drinking water treatment plants (DWTPs) were analyzed as part of a two-phase study to determine whether chemical and microbial constituents, many of which are considered contaminants of emerging concern, were detectable in the waters. Of the 84 chemicals monitored in the 9 Phase I DWTPs, 27 were detected at least once in the source water, and 21 were detected at least once in treated drinking water. In Phase II, which was a broader and more comprehensive assessment, 247 chemical and microbial analytes were measured in 25 DWTPs, with 148 detected at least once in the source water, and 121 detected at least once in the treated drinking water. The frequency of detection was often related to the analyte’s contaminant class, as pharmaceuticals and anthropogenic waste indicators tended to be infrequently detected and more easily removed during treatment, while per and polyfluoroalkyl substances and inorganic constituents were both more frequently detected and, overall, more resistant to treatment. The data collected as part of this project will be used to help inform evaluation of unregulated contaminants in surface water, groundwater, and drinking water.

An approach for integrating toxicogenomic data in risk assessment: the dibutyl phthalate case study.

An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose-response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions--Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?--were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment.

Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set ☆

A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts led to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data.

Human health screening and public health significance of contaminants of emerging concern detected in public water supplies

The source water and treated drinking water from twenty five drinking water treatment plants (DWTPs) across the United States were sampled in 2010-2012. Samples were analyzed for 247 contaminants using 15 chemical and microbiological methods. Most of these contaminants are not regulated currently either in drinking water or in discharges to ambient water by the U. S. Environmental Protection Agency (USEPA) or other U.S. regulatory agencies. This analysis shows that there is little public health concern for most of the contaminants detected in treated water from the 25 DWTPs participating in this study. For vanadium, the calculated Margin of Exposure (MOE) was less than the screening MOE in two DWTPs. For silicon, the calculated MOE was less than the screening MOE in one DWTP. Additional study, for example a national survey may be needed to determine the number of people ingesting vanadium and silicon above a level of concern. In addition, the concentrations of lithium found in treated water from several DWTPs are within the range previous research has suggested to have a human health effect. Additional investigation of this issue is necessary. Finally, new toxicological data suggest that exposure to manganese at levels in public water supplies may present a public health concern which will require a robust assessment of this information.

Exposure-response modeling of non-cancer effects in humans exposed to Libby Amphibole Asbestos; update

The United States Environmental Protection Agency (EPA) developed a quantitative exposure-response model for the non-cancer effects of Libby Amphibole Asbestos (LAA) (EPA, 2014). The model is based on the prevalence of localized pleural thickening (LPT) in workers exposed to LAA at a workplace in Marysville, Ohio (Lockey et al., 1984; Rohs et al., 2008). Recently, Lockey et al. (2015a) published a follow-up study of surviving Marysville workers. The data from this study increases the number of cases of LPT and extends the observation period for a number of workers, thereby providing a strengthened data set to define and constrain the optimal exposure-response model for non-cancer effects from inhalation exposure to LAA. The new data were combined with the previous data to update the exposure-response modeling for LPT. The results indicate that a bivariate model using cumulative exposure and time since first exposure is appropriate, and the benchmark concentration is similar to the findings previously reported by EPA (2014). In addition, the data were also used to develop initial exposure-response models for diffuse pleural thickening (DPT) and small interstitial opacities (SIO).

Per- and polyfluoroalkyl substances in source and treated drinking waters of the United States

Contaminants of emerging concern (CECs), including per- and polyfluoroalkyl substances (PFAS), are of interest to regulators, water treatment utilities, the general public and scientists. This study measured 17 PFAS in source and treated water from 25 drinking water treatment plants (DWTPs) as part of a broader study of CECs in drinking water across the United States. PFAS were quantitatively detected in all 50 samples, with summed concentrations of the 17 PFAS ranging from <1 ng/L to 1102 ng/L. The median total PFAS concentration was 21.4 ng/L in the source water and 19.5 ng/L in the treated drinking water. Comparing the total PFAS concentration in source and treated water at each location, only five locations demonstrated statistically significant differences (i.e. P < 0.05) between the source and treated water. When the perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) concentrations in the treated drinking water are compared to the existing US Environmental Protection Agency’s PFOA and PFOS drinking water heath advisory of 70 ng/L for each chemical or their sum one DWTP exceeded the threshold. Six of the 25 DWTPs were along twolarge rivers. The DWTPswithin each of the river systems had specific PFAS profiles, with the three DWTPs from one river being dominated by PFOA, while three DWTPs on the second river were dominated by perfluorobutyric acid (PFBA).