Recommended Reference Values for Risk Assessment of Oral Exposure to Copper.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.

Implications of sample size, rareness, and commonness for derivation of environmental benchmarks and criteria from field and laboratory data.

Tabulations of numerical concentration-based environmental benchmarks are commonly used to inform decisions on managing chemical exposures. Benchmarks are usually set at levels below which there is a low likelihood of adverse effects. Given the widespread use of tables of benchmarks, it is reasonable to expect that they are adequately reliable and fit for purpose. The degree to which a derived benchmark reflects an actual effect level or statistical randomness is critically important for the reliability of a numerical benchmark value. These expectations may not be met for commonly-used benchmarks examined in this study. Computer simulations of field sampling and toxicity testing reveal that small sample size and confounding from uncontrolled factors that affect the interpretation of toxic effects contribute to uncertainties that might go unrecognized when deriving benchmarks from data sets. The simulations of field data show that it is possible to derive a benchmark even when no toxicity is present. When toxicity is explicitly included in simulations, imposed effect threshold levels could not always be accurately determined. Simulations were also used to examine the influence of mixtures of chemicals on the determination of toxicity thresholds of chemicals within the mixtures. The simulations showed that data sets that appear large and robust can contain many smaller data sets associated with specific biota or chemicals. The sub-sets of data with small sample sizes can contribute to considerable statistical uncertainty in the determination of effects thresholds and can indicate that effects are present when they are absent. The simulations also show that less toxic chemicals may appear toxic when they are present in mixtures with more toxic chemicals. Because of confounding in the assignment of toxicity to individuals chemicals within mixtures, simulations showed that derived toxicity thresholds can be less than the actual toxicity thresholds. A set of best practices is put forward to guard against the potential problems identified by this work. These include conducting an adequate process of determining and implementing Data Quality Objectives (DQOs), evaluating implications of sample size, designing appropriate sampling and evaluation programs based on this information, using an appropriate tiered evaluation strategy that considers the uncertainties, and employing a weight of evidence approach to narrow the uncertainties to manageable and identified levels. The work underscores the importance of communicating the uncertainties associated with numerical values commonly included in tables for screening and risk assessment purposes to better inform decisions.

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007-2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

Scientific integrity issues in Environmental Toxicology and Chemistry: Improving research reproducibility, credibility, and transparency.

High-profile reports of detrimental scientific practices leading to retractions in the scientific literature contribute to lack of trust in scientific experts. Although the bulk of these have been in the literature of other disciplines, environmental toxicology and chemistry are not free from problems. While we believe that egregious misconduct such as fraud, fabrication of data, or plagiarism is rare, scientific integrity is much broader than the absence of misconduct. We are more concerned with more commonly encountered and nuanced issues such as poor reliability and bias. We review a range of topics including conflicts of interests, competing interests, some particularly challenging situations, reproducibility, bias, and other attributes of ecotoxicological studies that enhance or detract from scientific credibility. Our vision of scientific integrity encourages a self-correcting culture that promotes scientific rigor, relevant reproducible research, transparency in competing interests, methods and results, and education. Integr Environ Assess Manag 2019;00:000-000. © 2019 SETAC.

Interlaboratory comparison of a reduced volume marine sediment toxicity test method using the amphipod Ampelisca abdita.

The U.S. Environmental Protection Agency has standardized methods for performing acute marine amphipod sediment toxicity tests. A test design reducing sediment volume from 200 to 50 ml and overlying water from 600 to 150 ml was recently proposed. An interlaboratory comparison was conducted to evaluate the precision of this reduced sediment volume toxicity test method using the marine amphipod Ampelisca abdita. A negative control and three sediment samples of varying degrees of toxicity ranging from low to high were tested by six laboratories. Complete agreement was reached in rank of relative toxicity for all samples tested by five out of six laboratories. Test acceptability for control survival was achieved by all laboratories, and 69% agreement in classification of the sediments as toxic or nontoxic was documented. Coefficients of variation in all test samples were similar to those reported in other interlaboratory studies using marine amphipods. Results of this study indicate that the reduced sediment volume test using A. abdita is a reliable and precise measure of acute toxicity in marine sediment samples.