Medaka (Oryzias latipes) Multigeneration Test with Triclosan.

The medaka extended one-generation reproduction test (MEOGRT) is a tier-2 study in the US Environmental Protection Agency's Endocrine Disruptor Screening Program and a level-5 study in the Organisation for Economic Co-operation and Development's conceptual framework. Integrating nonspecific apical and endocrine-specific mechanistic endpoints, results of a MEOGRT can be used, with other data, in a weight-of-evidence evaluation to establish a dose-response relationship for risk assessment and identify potential causal relationships between an endocrine mode of action and adverse effects. The MEOGRT test design was used to evaluate the multigenerational effects of the antimicrobial agent triclosan. Japanese medaka were exposed to nominal concentrations of 1.4, 2.8, 5.6, 11, and 23 µg/L triclosan and a dilution water control starting with adult medaka (F0) through hatch in the second generation (F2). No consistent or concentration-related responses occurred in the 182-d test that suggested an endocrine-mediated effect. There were no impacts on hepatic vitellogenin, secondary sex characteristics, or sex ratio that were linked to an adverse reproductive outcome. Histopathological responses were consistent with a toxic or stress effect, particularly when considered in context with observed reductions in growth. The overall population-relevant no-observed-effect concentration was 11 µg/L based on effects on growth. The results of the present study support a previously conducted weight-of-evidence evaluation concluding that triclosan does not act as an agonist or antagonist within estrogen, androgen, thyroid, or steroidogenic pathways. Environ Toxicol Chem 2019;38:1770-1783. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

High-throughput screening and environmental risk assessment: State of the science and emerging applications.

In 2007 the United States National Research Council (NRC) published a vision for toxicity testing in the 21st century that emphasized the use of in vitro high-throughput screening (HTS) methods and predictive models as an alternative to in vivo animal testing. In the present study we examine the state of the science of HTS and the progress that has been made in implementing and expanding on the NRC vision, as well as challenges to implementation that remain. Overall, significant progress has been made with regard to the availability of HTS data, aggregation of chemical property and toxicity information into online databases, and the development of various models and frameworks to support extrapolation of HTS data. However, HTS data and associated predictive models have not yet been widely applied in risk assessment. Major barriers include the disconnect between the endpoints measured in HTS assays and the assessment endpoints considered in risk assessments as well as the rapid pace at which new tools and models are evolving in contrast with the slow pace at which regulatory structures change. Nonetheless, there are opportunities for environmental scientists and policymakers alike to take an impactful role in the ongoing development and implementation of the NRC vision. Six specific areas for scientific coordination and/or policy engagement are identified. Environ Toxicol Chem 2019;38:12-26. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Hypothesis-driven weight-of-evidence analysis for the endocrine disruption potential of benzene.

Exposure to benzene has many sources, from gasoline refueling to tobacco combustion. Although the toxicology of benzene is well studied, the potential for environmental exposure and a heightened interest in identifying substances that may cause toxicity by interacting with the endocrine systems of humans and wildlife resulted in benzene being placed on the second list of chemicals for possible screening under the USEPA's Endocrine Disruptor Screening Program. Therefore, we conducted a thorough, systematic literature search and used a weight-of-evidence methodology to test hypotheses regarding the potential for benzene to act via estrogen, androgen, thyroid, and steroidogenic pathways. The methodology included an assessment of data quality and a semi-quantitative weighting of endocrine-responsive endpoints measured in various types of studies according to their relevance for evaluating each hypothesis. This maximized use of all relevant and reliable literature on benzene and enabled a transparent comparison of evidence supporting and opposing each hypothesized mode of action. While benzene affected reproductive organ weights and histopathology in a few studies, there was no consistent pattern of effects suggestive of an estrogen, androgen, thyroid or steroidogenic mode of action. Based on data from multiple animal species, benzene appears to lack endocrine activity by these pathways.

Distinguishing between endocrine disruption and non-specific effects on endocrine systems.

The endocrine system is responsible for growth, development, maintaining homeostasis and for the control of many physiological processes. Due to the integral nature of its signaling pathways, it can be difficult to distinguish endocrine-mediated adverse effects from transient fluctuations, adaptive/compensatory responses, or adverse effects on the endocrine system that are caused by mechanisms outside the endocrine system. This is particularly true in toxicological studies that require generation of effects through the use of Maximum Tolerated Doses (or Concentrations). Endocrine-mediated adverse effects are those that occur as a consequence of the interaction of a chemical with a specific molecular component of the endocrine system, for example, a hormone receptor. Non-endocrine-mediated adverse effects on the endocrine system are those that occur by other mechanisms. For example, systemic toxicity, which perturbs homeostasis and affects the general well-being of an organism, can affect endocrine signaling. Some organs/tissues can be affected by both endocrine and non-endocrine signals, which must be distinguished. This paper examines in vitro and in vivo endocrine endpoints that can be altered by non-endocrine processes. It recommends an evaluation of these issues in the assessment of effects for the determination of endocrine disrupting properties of chemicals. This underscores the importance of using a formal weight of evidence (WoE) process to evaluate potential endocrine activity.

Distributions of concentrations of bisphenol A in North American and European surface waters and sediments determined from 19 years of monitoring data.

Concentrations of bisphenol A (BPA) in North American and European fresh and marine surface waters and sediments were analyzed to quantify environmental levels and evaluate trends over the years 1996-2014. In North American surface water and sediment, 68% of 1030 weighted observations were below a detection limit (varied widely between studies). In Europe, 33% of 5057 weighted observations were below a detection limit. In North America and Europe, 50th percentile concentrations were 0.005 µg L-1 and 0.029 µg L-1 in freshwater and 0.0011 µg L-1 and 0.007 µg L-1 in marine water. The 95th percentile concentrations in freshwater were the same in North America and Europe at 0.30 µg L-1 and were 0.024 µg L-1 and 0.15 µg L-1 in marine water, respectively. Fiftieth percentile concentrations in North American and European freshwater sediment were 0.7 ng g-1 dry weight (dw) and 7.0 ng g-1 dw and in marine sediment were 1.0 ng g-1 dw and <0.03 ng g-1 dw, respectively. The 95th percentile concentrations were 39 ng g-1 dw and 177 ng g-1 dw in freshwater sediment and 100 ng g-1 dw and 63 ng g-1 dw in marine sediment, respectively. Most concentrations were below published chronic toxicity values or regulatory limits. BPA freshwater concentrations in both regions appear to have remain relatively unchanged over the 19 year period during which BPA production and use in polycarbonate plastic production increased significantly. There is no clear correlation between BPA or polycarbonate production and BPA levels in surface waters.

Life-cycle studies with 2 marine species and bisphenol A: The mysid shrimp (Americamysis bahia) and sheepshead minnow (Cyprinodon variegatus).

Bisphenol A (BPA) is a high production volume compound primarily used to produce epoxy resins and polycarbonate plastic. Exposure to low concentrations of BPA occurs in freshwater and marine systems, primarily from wastewater treatment plant discharges. The dataset for chronic toxicity of BPA to freshwater organisms includes studies on fish, amphibians, invertebrates, algae, and aquatic plants. To broaden the dataset, a 1.5-generation test with sheepshead minnow (Cyprinodon variegatus) and a full life-cycle test with mysid shrimp (Americamysis bahia) were conducted. Testing focused on apical endpoints of survival, growth and development, and reproduction. The respective no-observed-effect concentration (NOEC) and lowest-observed-effect concentration (LOEC) values of 170 and 370 µg/L for mysid and 66 and 130 µg/L for sheepshead were based on reduced fecundity. The hazardous concentrations for 5% of the species (HC5) values of 18 µg/L were calculated from species sensitivity distributions (SSDs) with freshwater-only data and combined freshwater and marine data. Inclusion of marine data resulted in no apparent difference in SSD shape, R2 values for the distributions, or HC5 values. Upper-bound 95th percentile concentrations of BPA measured in marine waters of North America and Europe (0.024 and 0.15 µg/L, respectively) are below the HC5 value of 18 µg/L. These results suggest that marine and freshwater species are of generally similar sensitivity and that chronic studies using a diverse set of species can be combined to assess the aquatic toxicity of BPA. Environ Toxicol Chem 2018;37:398-410. © 2017 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.

Recommended approaches to the scientific evaluation of ecotoxicological hazards and risks of endocrine-active substances.

A SETAC Pellston Workshop® "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17α-ethinylestradiol, perchlorate, propiconazole, 17ß-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Hypothesis-driven weight-of-evidence analysis of endocrine disruption potential: a case study with triclosan.

Triclosan is an antimicrobial agent used in a range of consumer products, such as deodorants, oral care, clothing, and household items. As with many consumer products, triclosan can be rinsed down the drain and transported to wastewater treatment plants. While most is eliminated during activated sludge sewage treatment by biodegradation and adsorption, some triclosan enters the aquatic environment and may expose wildlife. Given the potential for exposure to both humans and wildlife, resolving whether triclosan is endocrine active is important due to growing concerns about potential adverse public health and environmental effects of endocrine-disrupting substances. A weight of evidence (WoE) analysis focusing on specific hypotheses related to interaction with estrogen, androgen, and thyroid hormone pathways, and steroidogenesis was applied to triclosan. This WoE procedure involved systematic consideration of each endpoint, focused on screening level studies in the US Endocrine Disruptor Screening Program, as well as those in levels 1 through 5 of the OECD Conceptual Framework. This was followed by a semiquantitative relevance weighting of each endpoint to a given hypothesis to reach scientifically justified conclusions. Use of all relevant and reliable information and consistent observations in multiple studies strengthen support for or against each mode of action hypothesis. Using data from multiple animal species and in vitro systems, this systematic and transparent WoE assessment indicated that triclosan is not acting as an agonist or antagonist within the estrogen, androgen, thyroid, or steroidogenic pathways and is not impacting endocrine pathways as a lead or primary mode of toxicity.

Challenges in assigning endocrine-specific modes of action: Recommendations for researchers and regulators.

As regulatory programs evaluate substances for their endocrine-disrupting properties, careful study design and data interpretation are needed to distinguish between responses that are truly endocrine specific and those that are not. This is particularly important in regulatory environments where criteria are under development to identify endocrine-disrupting properties to enable hazard-based regulation. Irrespective of these processes, most jurisdictions use the World Health Organization/International Programme on Chemical Safety definition of an endocrine disruptor, requiring that a substance is demonstrated to cause a change in endocrine function that consequently leads to an adverse effect in an intact organism. Such a definition is broad, and at its most cautious might capture many general mechanisms that would not specifically denote an endocrine disruptor. In addition, endocrine responses may be adaptive in nature, designed to maintain homeostasis rather than induce an irreversible adverse effect. The likelihood of indirect effects is increased in (eco)toxicological studies that require the use of maximum tolerated concentrations or doses, which must produce some adverse effect. The misidentification of indirect effects as truly endocrine mediated has serious consequences for prompting animal- and resource-intensive testing and regulatory consequences. To minimize the risk for misidentification, an objective and transparent weight-of-evidence procedure based on biological plausibility, essentiality, and empirical evidence of key events in an adverse outcome pathway is recommended to describe the modes of action that may be involved in toxic responses in nontarget organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the weight of evidence. A recommended set of questions is proffered to help guide researchers and regulators in discerning endocrine and nonendocrine responses. Although many examples provided in this study are based on ecotoxicology, the majority of the concepts and processes are applicable to both environmental and human health assessments. Integr Environ Assess Manag 2017;13:280-292. © 2016 SETAC.

Characterizing the effects of bisphenol A on sediment-dwelling benthic organisms.

Bisphenol A (BPA) is a high production volume chemical intermediate used primarily in the production of polycarbonate plastics and epoxy resins. It primarily enters surface water and sediment via effluent discharges during its manufacture and use. The physical properties of BPA suggest that sediment is a potential sink and may result in exposure to benthic organisms. Currently there are no studies measuring the chronic toxicity of BPA to benthic organisms via direct sediment exposure. The present study examined the chronic toxicity of BPA to 3 commonly used test organisms that are generally representative of invertebrates occupying the base of the benthic food web and for which standardized testing protocols are available: the oligochaete Lumbriculus variegatus (mean numbers and biomass), the midge Chironomus riparius (emergence and development rate), and the estuarine amphipod Leptocheirus plumulosus (survival, growth, and reproduction). No-observed-effect concentrations (NOECs) for the 3 species ranged from 12 mg/kg to 54 mg/kg dry weight. All NOEC values were higher than all measured concentrations of BPA in freshwater and marine sediments reported in reliable, fully reported studies from North America and Europe from the 1990s to the present. For the first time, there are studies with BPA measuring the chronic toxicity to 3 taxa of sediment dwelling invertebrates, which are suitable to support region-specific risk assessments.

Characterization of ecological risks from environmental releases of decamethylcyclopentasiloxane (D5).

Decamethylcyclopentasiloxane (D5) is used in personal care products and industrial applications. The authors summarize the risks to the environment from D5 based on multiple lines of evidence and conclude that it presents negligible risk. Laboratory and field studies show that D5 is not toxic to aquatic organisms or benthic invertebrates up to its solubility limit in water or porewater or its sorptive capacity in sediment. Comparison of lipid-normalized internal concentrations with measured concentrations in benthos indicates that field-collected organisms do not achieve toxic levels of D5 in their tissues, suggesting negligible risk. Exposure to D5 resulted in a slight reduction of root biomass in barley at test concentrations 2 orders of magnitude greater than measured D5 levels in biosolids-amended soils and more than twice as high as the maximum calculated sorptive capacity of the soil. No effects were observed in soil invertebrates exposed to similar concentrations, indicating that D5 poses a de minimis risk to the terrestrial environment. High rates of metabolism and elimination of D5 compared with uptake rates from food results in biodilution in the food web rather than biomagnification, culminating in de minimis risk to higher trophic level organisms via the food chain. A fugacity approach substantiates all conclusions that were made on a concentration basis.

Short-term fish reproduction assays with methyl tertiary butyl ether with zebrafish and fathead minnow: Implications for evaluation of potential for endocrine activity.

The authors report on short-term fish reproduction assays in zebrafish and fathead minnow conducted to examine the potential for methyl tertiary butyl ether (MTBE) to cause effects on the endocrine system. Both studies were performed under good laboratory practice and in accordance with Organisation for Economic Co-operation and Development and US Environmental Protection Agency test guidelines. The results of the first study demonstrated that exposure to a high test concentration (147 mg/L) of MTBE impaired reproductive output of female zebrafish, evident by a reduction in fecundity. Based on the endpoints evaluated in the present study however, there was no supporting evidence to indicate that this effect was caused by disruption of or interaction with the endocrine system. In the second study, fathead minnows exposed to a wider but lower range of test concentrations showed no effects on any reproductive parameter of male or female fish, at the maximum recommended testing concentration of 100 mg/L (62 mg/L measured). The results of these 2 guideline studies indicate that MTBE does not interact with the hypothalamic-pituitary-gonadal axis of zebrafish or fathead minnow.

Hypothesis-driven weight of evidence analysis to determine potential endocrine activity of MTBE.

Endocrine-related endpoints in animals have been reported to respond to high doses of methyl tertiary-butyl ether (MTBE), however, a systematic and transparent evaluation of endocrine potential has not been published. Resolving whether MTBE exhibits endocrine activity is important given regulatory and public interest in endocrine disrupting substances and their potential for causing adverse effects in humans or wildlife. A weight-of-evidence (WoE) analysis was conducted, focusing on hypotheses related to the potential for MTBE to interact with estrogen, androgen, and thyroid pathways, and steroidogenesis. To reach scientifically justified conclusions based on the totality of evidence, this WoE procedure involved a semi-quantitative relevance weighting of each endpoint for each hypothesis and systematic consideration of each endpoint in various study designs. This procedure maximized use of an extensive body of relevant and reliable literature on MTBE with evidence supporting or opposing a given mode of action hypothesis. Evaluating the strength and consistency of observations from many MTBE studies also provided a way to assess whether high doses used in experiments with MTBE confound identification of direct endocrine system responses. Based on results of studies using mammalian and fish models and in vitro screening assays, this WoE assessment reveals that MTBE lacks direct endocrine activity.

Responses of the steroidogenic pathway from exposure to methyl-tert-butyl ether and tert-butanol.

Methyl tertiary-butyl ether (MTBE) is a solvent and fuel additive included in reformulated gasoline to increase combustion efficiency. While widespread use in motor fuels in the U.S. was discontinued after MTBE was detected in surface and ground waters due to concerns about environmental persistence and water quality, it is still manufactured in the U.S. for export. Questions concerning the etiology of rat Leydig cell and mouse liver tumors identified in extremely high dose cancer studies have led to an interest in evaluating potential hormonal imbalances and endocrine system involvement. To address the possibility that MTBE or its metabolite, tert-butanol (TBA), are interacting with components of the endocrine system that are involved in steroidogenesis a number of targeted experiments were performed focusing mostly on the primary gonadal steroids, estradiol and testosterone. The goal of the experiments was to gain a better understanding of potential interactions with the steroidogenic pathway, including effects specifically on aromatase, the P450 enzyme that converts testosterone to estradiol. In three GLP-compliant in vitro guideline studies, MTBE and TBA were classified as non-binders to the androgen receptor, were classified negative for effects on testosterone and estradiol in the steroidogenesis assay, and were classified as non-inhibitors of aromatase activity. In three 14-day in vivo experiments involving gavaging of male Sprague-Dawley rats with doses of MTBE ranging from 400 to 1,500 mg/kg bw/day, the lack of definitive and consistent supporting statistically significant findings in steroid hormone measurements and aromatase activity and mRNA measured in liver and testis microsomes further suggested that it is unlikely that MTBE is interacting with the endocrine system directly. Evidence of other underlying systemic effects were also seen, including reduced body weight gain, increased adrenal weights, and elevated corticosterone suggestive of a more general stress response. Taken together, the results from these studies suggest that MTBE and TBA do not directly impact the steroidogenic pathways involved in estrogen and androgen production.

Relevance weighting of tier 1 endocrine screening endpoints by rank order.

Weight of evidence (WoE) approaches are recommended for interpreting various toxicological data, but few systematic and transparent procedures exist. A hypothesis-based WoE framework was recently published focusing on the U.S. EPA's Tier 1 Endocrine Screening Battery (ESB) as an example. The framework recommends weighting each experimental endpoint according to its relevance for deciding eight hypotheses addressed by the ESB. Here we present detailed rationale for weighting the ESB endpoints according to three rank ordered categories and an interpretive process for using the rankings to reach WoE determinations. Rank 1 was assigned to in vivo endpoints that characterize the fundamental physiological actions for androgen, estrogen, and thyroid activities. Rank 1 endpoints are specific and sensitive for the hypothesis, interpretable without ancillary data, and rarely confounded by artifacts or nonspecific activity. Rank 2 endpoints are specific and interpretable for the hypothesis but less informative than Rank 1, often due to oversensitivity, inclusion of narrowly context-dependent components of the hormonal system (e.g., in vitro endpoints), or confounding by nonspecific activity. Rank 3 endpoints are relevant for the hypothesis but only corroborative of Ranks 1 and 2 endpoints. Rank 3 includes many apical in vivo endpoints that can be affected by systemic toxicity and nonhormonal activity. Although these relevance weight rankings (WREL ) necessarily involve professional judgment, their a priori derivation enhances transparency and renders WoE determinations amenable to methodological scrutiny according to basic scientific premises, characteristics that cannot be assured by processes in which the rationale for decisions is provided post hoc.

Lessons learned, challenges, and opportunities: the U.S. Endocrine Disruptor Screening Program.

In 1996, the U.S. Congress passed the Food Quality Protection Act and amended the Safe Drinking Water Act (SDWA) requiring the U.S. Environmental Protection Agency (EPA) to implement a screening program to investigate the potential of pesticide chemicals and drinking water contaminants to adversely affect endocrine pathways. Consequently, the EPA launched the Endocrine Disruptor Screening Program (EDSP) to develop and validate estrogen, androgen, and thyroid (EAT) pathway screening assays and to produce standardized and harmonized test guidelines for regulatory application. In 2009, the EPA issued the first set of test orders for EDSP screening and a total of 50 pesticide actives and 2 inert ingredients have been evaluated using the battery of EDSP Tier 1 screening assays (i.e., five in vitro assays and six in vivo assays). To provide a framework for retrospective analysis of the data generated and to collect the insight of multiple stakeholders involved in the testing, more than 240 scientists from government, industry, academia, and non-profit organizations recently participated in a workshop titled "Lessons Learned, Challenges, and Opportunities: The U.S. Endocrine Disruptor Screening Program." The workshop focused on the science and experience to date and was organized into three focal sessions: (a) Performance of the EDSP Tier 1 Screening Assays for Estrogen, Androgen, and Thyroid Pathways; (b) Practical Applications of Tier 1 Data; and (c) Indications and Opportunities for Future Endocrine Testing. A number of key learnings and recommendations related to future EDSP evaluations emanated from the collective sessions.

Adult fathead minnow, Pimephales promelas, partial life-cycle reproductive and gonadal histopathology study with bisphenol A.

Bisphenol A (BPA) is an intermediate used to produce epoxy resins and polycarbonate plastics. Although BPA degrades rapidly in the environment with aquatic half-lives from 0.5 to 6 d, it can be found in aquatic systems because of widespread use. To evaluate potential effects from chronic exposure, fathead minnows were exposed for 164 d to nominal concentrations of 1, 16, 64, 160, and 640 µg/L BPA. Population-level endpoints of survival, growth, and reproduction were assessed with supplemental endpoints (e.g., vitellogenin, gonad histology), including gonad cell type assessment and quantification. No statistically significant changes in growth, gonad weight, gonadosomatic index, or reproduction variables (e.g., number of eggs and spawns, hatchability) were observed; however, there was a significant impact on male survival at 640 µg/L. Vitellogenin increased in both sexes at 64 µg/L or higher. Gonad cell type frequencies were significantly different from controls at 160 µg/L or higher in males with a slight decrease in spermatocytes compared with less mature cell types, and at 640 µg/L in females with a slight decrease in early vitellogenic cells compared with less mature cells. The decrease in spermatocytes did not correspond to a decrease in the most mature sex cell type (spermatozoa) and did not impair male fertility, as hatchability was not impacted. Overall, marginal shifts in gametogenic cell maturation were not associated with any statistically significant effects on population-relevant reproductive endpoints (growth, fecundity, and hatchability) at any concentration tested.

Tissue-based risk assessment of cyclic volatile methyl siloxanes.

Cyclic volatile methyl siloxanes (cVMS) are important consumer materials that are used in personal care products and industrial applications. These compounds have gained increased attention in recent years following the implementation of chemical legislation programs worldwide. Industry-wide research programs are being conducted to characterize the persistence, bioaccumulation, and toxicity (PBT) properties of cVMS materials. As part of this larger effort, a tissue-based risk assessment was performed to further inform the regulatory decision-making process. Measured tissue concentrations of cVMS compounds in fish and benthic invertebrates are compared with critical target lipid body burdens (CTLBBs) as estimated with the target lipid model (TLM) to evaluate risk. Acute and chronic toxicity data for cVMS compounds are compared with data for nonpolar organic chemicals to validate application of the TLM in this effort. The analysis was extended to estimate the contribution from metabolites to the overall cVMS-derived tissue residues using a food chain model calibrated to laboratory and field data. Concentrations of cVMS materials in biota from several trophic levels (e.g., invertebrates, fish) are well below the estimated CTLBBs associated with acute and chronic effects. This analysis, when combined with the limited biomagnification potential for cVMS compounds that was observed in the field, suggests that there is little risk of adverse effects from cVMS materials under present-day emission levels.

Information Quality in Regulatory Decision Making: Peer Review versus Good Laboratory Practice.

BACKGROUND: There is an ongoing discussion on the provenance of toxicity testing data regarding how best to ensure its validity and credibility. A central argument is whether journal peer-review procedures are superior to Good Laboratory Practice (GLP) standards employed for compliance with regulatory mandates. OBJECTIVE: We sought to evaluate the rationale for regulatory decision making based on peer-review procedures versus GLP standards. METHOD: We examined pertinent published literature regarding how scientific data quality and validity are evaluated for peer review, GLP compliance, and development of regulations. DISCUSSION: Some contend that peer review is a coherent, consistent evaluative procedure providing quality control for experimental data generation, analysis, and reporting sufficient to reliably establish relative merit, whereas GLP is seen as merely a tracking process designed to thwart investigator corruption. This view is not supported by published analyses pointing to subjectivity and variability in peer-review processes. Although GLP is not designed to establish relative merit, it is an internationally accepted quality assurance, quality control method for documenting experimental conduct and data. CONCLUSIONS: Neither process is completely sufficient for establishing relative scientific soundness. However, changes occurring both in peer-review processes and in regulatory guidance resulting in clearer, more transparent communication of scientific information point to an emerging convergence in ensuring information quality. The solution to determining relative merit lies in developing a well-documented, generally accepted weight-of-evidence scheme to evaluate both peer-reviewed and GLP information used in regulatory decision making where both merit and specific relevance inform the process.