Karen A. Hogan

Risk assessment of formaldehyde

Abstract In April 1987, the Environmental Protection Agency (EPA) issued the “Assessment of Health Risks to Garment Workers and Certain Home Residents from Exposure to Formaldehyde” in which formaldehyde was classified as a carcinogen and an irritant to the eyes and respiratory tract. A quantitative risk assessment for cancer was presented. A more current document, a draft released in 1991, incorporates some additional data on the epidemiology and toxicology of formaldehyde that the EPA has received since completion of the earlier assessment, and examines the impact of this information on the estimates of health risks following exposure to airborne formaldehyde. For noncancer effects, the new data support earlier conclusions with regard to the irritant effects of formaldehyde and the dose-response gradient for these effects. The cancer assessment incorporates the use of a molecular dosimeter for the derivation of risk estimates. Tissue levels of this dosimeter, a covalent cross-link product of formaldehyde and DNA-protein (DPX), are available from rats and monkeys. The risk estimates obtained with this dosimeter are considerably lower than those obtained by conventional approaches.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties.

Approaches to cancer assessment in EPA's Integrated Risk Information System

The U.S. Environmental Protection Agencys (EPA) Integrated Risk Information System (IRIS) Program develops assessments of health effects that may result from chronic exposure to chemicals in the environment. The IRIS database contains more than 540 assessments. When supported by available data, IRIS assessments provide quantitative analyses of carcinogenic effects. Since publication of EPAs 2005 Guidelines for Carcinogen Risk Assessment, IRIS cancer assessments have implemented new approaches recommended in these guidelines and expanded the use of complex scientific methods to perform quantitative dose-response assessments. Two case studies of the application of the mode of action framework from the 2005 Cancer Guidelines are presented in this paper. The first is a case study of 1,2,3-trichloropropane, as an example of a chemical with a mutagenic mode of carcinogenic action thus warranting the application of age-dependent adjustment factors for early-life exposure; the second is a case study of ethylene glycol monobutyl ether, as an example of a chemical with a carcinogenic action consistent with a nonlinear extrapolation approach. The use of physiologically based pharmacokinetic (PBPK) modeling to quantify interindividual variability and account for human parameter uncertainty as part of a quantitative cancer assessment is illustrated using a case study involving probabilistic PBPK modeling for dichloromethane. We also discuss statistical issues in assessing trends and model fit for tumor dose-response data, analysis of the combined risk from multiple types of tumors, and application of life-table methods for using human data to derive cancer risk estimates. These issues reflect the complexity and challenges faced in assessing the carcinogenic risks from exposure to environmental chemicals, and provide a view of the current trends in IRIS carcinogenicity risk assessment.

High-to-Low Dose Extrapolation: Issues and Approaches

The practice of risk assessment at the U.S. Environmental Protection Agency (USEPA) often includes the estimation of risks at exposures or doses below the range of observation (USEPA 2004), a challenge given the type of data typically available from standard toxicological paradigms. For instance, a number of programs involve regulation at the 10−6 to 10−4 risk level—risks (and by implication, exposures) that are well below those observable in experimental or epidemiological settings. As a general rule, fewer studies are available as one goes to lower and lower exposures. Rodent bioassays and pharmacokinetic studies and human occupational studies are typically the most plentiful, while at the same time probing exposures often several orders of magnitude above those found in the environment. At the other end of the spectrum, environmental epidemiology and exposure biomarker studies may begin to probe exposures of regulatory interest, but are currently few in number. Although in vitro studies have typically also been at higher exposures, data from “omics” technologies may potentially expand the availability of data in the “low dose” range. When considering what “low-dose extrapolation” means, it is instructive to consider the difference between “individual” dose-response (i.e ., the probability for a particular individual to exhibit an effect at a given dose) and “population” doseresponse (i.e ., the fraction of a variable population to exhibit an effect at a given dose). In particular, the same “population” dose-response might originate from different distributions of different-shaped “individual” dose-responses. At one extreme, a common interpretation for cancer dose response curves is “purely” stochastic with all individuals having the same probability of cancer at a given dose (USEPA

Approaches to human health risk assessment based on the signal-to-noise crossover dose.

We acknowledge the effort of Sand et al. (2011) in striving to develop a transparent, objective procedure for point of departure (POD) estimation, as encouraged by scien-tific review groups (National Research Council 2009). Although additional charac-teri-za-tion of the statistical properties of the signal-to-noise crossover dose (SNCD) may be warranted, the goal of Sand et al. (2011) appears consistent with the intent of the POD to charac-terize “the beginning of extrapolation to lower doses” [U.S. Environmental Protection Agency (EPA) 2005]. In this letter we respond to the authors’ illustration of their approach using cancer bio-assay data to develop reference doses (RfDs) that target a 1/1,000 risk through linear extrapolation from the POD by highlighting opportunities to augment their statistically based approach with biological considerations. For most carcinogens, the U.S. EPA develops cancer potency estimates as follows (U.S. EPA 2005). A POD associated with a benchmark response level (BMR) is derived and converted to human-equivalent units (incorporating information about cross-species dose scaling). The BMR is then divided by the human-equivalent POD to obtain a potency estimate, under the assumption that risks extrapolate linearly with doses below the BMR. For Sand et al. (2011), the upper-bound extra risk estimate (UERSNCD) is the BMR associated with the SNCD, but we recom-mend expressing SNCDs in human equivalents before deriving potency estimates. For nonlinear extrapolation resulting in a RfD (which the U.S. EPA uses for non-cancer effects and carcinogens with a threshold mode of action), Sand et al. (2011) chose to linearly extrapolate to a 1/1,000 risk in the test animal, which they considered analogous to applying a 100-fold uncertainty factor to a BMDL10 (lower bound on the benchmark dose corresponding to 10% extra risk). Several aspects of this proposal merit further considera-tion. First, margins of exposure much larger than 100-fold would be typical for cancer. Furthermore, whereas linear extrapo-la-tion involves extrapolation in the same population to a smaller level of effect, the standard uncertainty factor approach involves extrapolation across populations at a fixed level of effect. The alternative we propose separately accounts for these biologically unrelated processes. Motivating our proposal is the need highlighted by Sand et al. (2011) to clearly separate statistical factors supporting the level of effect associated with the POD while also fully incorporating biological considerations. We propose specifying “target” effect levels (TELs) associated with different end points based on biological considerations, independent of data set. The TELs could then be compared with the lowest practical BMR for a given data set—the UERSNCD used by Sand et al. The UERSNCD/TEL ratio is a diagnostic of the extent of extrapolation to the TEL. If UERSNCD ≤ TEL, then the BMD at the TEL does not involve extrapo-la-tion and can serve as the POD. For a UERSNCD > TEL, the greater the ratio, the greater the uncertainty in the BMD at the TEL from extrapo-la-tion below the SNCD. In this case, the SNCD could serve as the POD, and the gap between the UERSNCD and the TEL could be bridged by an additional factor (analo-gous to the LOAEL-to-NOAEL factor) or linear extrapolation. Then, inter-species, intra-species, and any other adjustments for deriving RfDs would be applied as usual. Thus, this approach separately takes into account biological considerations related to the severity of the end point (via the TEL), statistical considerations related to the study data (via the UERSNCD), and adjustments from the test species to sensitive humans (via uncertainty factors or chemical-specific adjustments). In sum, the work of Sand et al. (2011)advances the development of approaches for providing a transparent, objective method to demark where “extrapolation begins.” However, for human health risk assessment, we propose augmenting statistically based approaches so that inter- and intra-species adjustments and biological considerations relating to the end points are explicitly addressed. Although consensus on specifying TELs may be challenging, particularly for precursor or toxico-genomic end points, clearly separating biological and statistical considerations will enhance the transparency and consistency of chemical assessments.

Human Health Effects of Biphenyl: Key Findings and Scientific Issues.

Background: In support of the Integrated Risk Information System (IRIS), the U.S. Environmental Protection Agency (EPA) has evaluated the human health hazards of biphenyl exposure. Objectives: We review key findings and scientific issues regarding expected human health effects of biphenyl. Methods: Scientific literature from 1926 through September 2012 was critically evaluated to identify potential human health hazards associated with biphenyl exposure. Key issues related to the carcinogenicity and noncancer health hazards of biphenyl were examined based on evidence from experimental animal bioassays and mechanistic studies. Discussion: Systematic consideration of experimental animal studies of oral biphenyl exposure took into account the variety of study designs (e.g., study sizes, exposure levels, and exposure durations) to reconcile differing reported results. The available mechanistic and toxicokinetic evidence supports the hypothesis that male rat urinary bladder tumors arise through urinary bladder calculi formation but is insufficient to hypothesize a mode of action for liver tumors in female mice. Biphenyl and its metabolites may induce genetic damage, but a role for genotoxicity in biphenyl-induced carcinogenicity has not been established. Conclusions: The available health effects data for biphenyl provides suggestive evidence for carcinogenicity in humans, based on increased incidences of male rat urinary bladder tumors at high exposure levels and on female mouse liver tumors. Kidney toxicity is also a potential human health hazard of biphenyl exposure. Citation: Li Z, Hogan KA, Cai C, Rieth S. 2016. Human health effects of biphenyl: key findings and scientific issues. Environ Health Perspect 124:703–712; http://dx.doi.org/10.1289/ehp.1509730