Opportunities in Assessing and Regulating Organohalogen Flame Retardants (OFRs) as a Class in Consumer Products.

BACKGROUND: In 2015, the U.S. Consumer Product Safety Commission (CPSC) received and then, in 2017, granted a petition under the Federal Hazardous Substances Act to declare certain groups of consumer products as banned hazardous substances if they contain nonpolymeric, additive organohalogen flame retardants (OFRs). The petitioners asked the CPSC to regulate OFRs as a single chemical class with similar health effects. The CPSC later sponsored a National Academy of Sciences, Engineering, and Medicine (NASEM) report in 2019, which ultimately identified 161 OFRs and grouped them into 14 subclasses based on chemical structural similarity. In 2021, a follow-up discussion was held among a group of scientists from both inside and outside of the CPSC for current research on OFRs and to promote collaboration that could increase public awareness of CPSC work and support the class-based approach for the CPSC's required risk assessment of OFRs. OBJECTIVES: Given the extensive data collected to date, there is a need to synthesize what is known about OFR and how class-based regulations have previously managed this information. This commentary discusses both OFR exposure and OFR toxicity and fills some gaps for OFR exposure that were not within the scope of the NASEM report. The objective of this commentary is therefore to provide an overview of the OFR research presented at SOT 2021, explore opportunities and challenges associated with OFR risk assessment, and inform CPSC's work on an OFR class-based approach. DISCUSSION: A class-based approach for regulating OFRs can be successful. Expanding the use of read-across and the use of New Approach Methodologies (NAMs) in assessing and regulating existing chemicals was considered as a necessary part of the class-based process. Recommendations for OFR class-based risk assessment include the need to balance fire and chemical safety and to protect vulnerable populations, including children and pregnant women. The authors also suggest the CPSC should consider global, federal, and state OFR regulations. The lack of data or lack of concordance in toxicity data could present significant hurdles for some OFR subclasses. The potential for cumulative risks within or between subclasses, OFR mixtures, and metabolites common to more than one OFR all add extra complexity for class-based risk assessment. This commentary discusses scientific and regulatory challenges for a class-based approach suggested by NASEM. This commentary is offered as a resource for anyone performing class-based assessments and to provide potential collaboration opportunities for OFR stakeholders. https://doi.org/10.1289/EHP12725.

Plasticizer migration from children's toys, child care articles, art materials, and school supplies.

Dialkyl phthalates, including diisononyl phthalate (DINP), have been used as plasticizers in children's products made from polyvinyl chloride (PVC), such as teethers and toys. Children may be exposed to phthalates when handling or mouthing PVC products because plasticizers are not covalently bound. The Consumer Product Safety Improvement Act of 2008 prohibited certain phthalates from use in child care articles and children's toys. Thus, manufacturers have changed to other plasticizers or non-PVC plastics and there is interest in evaluating the potential health risks of alternative plasticizers. In 2008, CPSC staff purchased 63 children's products comprising 129 individual pieces (articles). Plastics identified FTIR included PVC, polypropylene, polyethylene, and acrylonitrile butadiene styrene. Plasticizers identified by in the 38 PVC articles included acetyltributyl citrate (ATBC) (20); di (2-ethylhexyl) terephthalate (DEHT) (14); 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINX) (13); 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TPIB) (9); di (2 ethyhexyl) phthalate (DEHP) (1); and DINP (1). Half of the tested articles contained multiple plasticizers. CPSC measured migration rates using the Joint Research Centre method. Migration rates correlated roughly with plasticizer concentration and inversely with the molecular mass of the plasticizer. We then combined the migration rates with data on mouthing duration to estimate children's exposure to plasticizers in toys and child care articles, and estimated margins of exposure. All margins of exposure were >1,000, suggesting a low risk potential. However, the plasticizers in this study have multiple uses. Exposure from other sources and routes of exposure will be considered in future work.

Risk assessment of oral exposure to diisononyl phthalate from children's products.

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.

PPARalpha agonist-induced rodent tumors: modes of action and human relevance.

Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.