Environmental exposure to perchlorate: A review of toxicology and human health.

Perchlorate pharmacology and toxicology studies date back at least 65 years in the peer-reviewed literature. Repeated studies in animals and humans have demonstrated perchlorate's mechanism of action, dose-response, and adverse effects over a range of doses. The first measurable effect of perchlorate is inhibition of iodine uptake to the thyroid gland. Adequate levels of thyroid hormones are critical for the development of the fetal nervous system. With sufficient dose and exposure duration, perchlorate can reduce thyroid hormones in the pregnant or non-pregnant woman via this mechanism. The developing fetus is the most sensitive life stage for chemical agents that affect iodide uptake to the thyroid. Perchlorate has a half-life of eight hours, is not metabolized, does not bioaccumulate, is not a mutagen or carcinogen, and is not reprotoxic or immunotoxic. More recently, epidemiological and biomonitoring studies have been published in the peer-reviewed literature characterizing the thyroidal effects of perchlorate and other goitrogens. While the results from most populations report no consistent association, a few studies report thyroidal effects at environmentally relevant levels of perchlorate. We reviewed the literature on health effects of perchlorate at environmental exposure levels, with a focus on exposures during pregnancy and neurodevelopmental effects. Based on the studies we reviewed, health effects are expected to only occur at doses substantially higher than environmental levels.

Repeated dose inhalation developmental toxicity study in rats exposed to cellulose insulation with boric acid additive.

Cellulose insulation (CI), a common building material, is a mixture of cellulose fibers and borates. Borates are approximately 20% of the product weight and act as a flame retardant. Given possible exposure to workers and consumers, an inhalation toxicity study was conducted following Organization for Economic Co-operation and Development (OECD) 414 for Prenatal Development Toxicity to evaluate if CI is a developmental toxicant. Pregnant female rats were exposed by nose-only inhalation to CI aerosols containing 20% boric acid for six h/day, from gestational day (GD) 6-19, and fetuses were evaluated for developmental parameters. Respirable CI was produced by grinding to produce respirable particles (MMAD 2.7-2.9 µm, geometric standard deviations (GSD) 1.9-2.6), which were then aerosolized. Target air concentrations were 15, 90, and 270 mg CI/m3. Controls were exposed to air only. Slight body weight reductions (average decrease <7% vs. control) were observed in male and female GD 20 fetuses in the mid and high dose groups. No embryo/fetal developmental toxicity or alterations in any other measured variable were reported at any dose. The no observed adverse effect level (NOAEL) for developmental outcomes was 270 mg/m3.

Exposure of the US Population to Nitrate, Thiocyanate, Perchlorate, and Iodine Based on NHANES 2005-2014.

Perchlorate, thiocyanate, nitrate, and iodide all have the same action of iodide uptake inhibition. Urinary samples were available for the US population through the National Health and Nutrition Examination Survey (NHANES) database for these compounds and were evaluated for the 2005 through 2014 time period. We were interested in whether exposures to the US population had changed since the mid-2000s. Given that these exposures were largely naturally derived and exposure was from food, we hypothesized that the levels of nitrate, thiocyanate, and perchlorate remained relatively stable over this time period. Additionally, we evaluated mean perchlorate equivalent concentrations (PEC) of all three goitrogens together. There was a significant decrease in urinary perchlorate from 2005 to 2014 (p < 0.01). Thiocyanate and iodide also decreased significantly (p < 0.01), but not nitrate (p = 0.35). PEC decreased since 2005 with contribution from perchlorate at less than 1%, while nitrate increased in contribution.

Exposure Assessment Study on Lithium-Ion Battery Fire in Explosion Test Room in Battery Testing Facility.

A lithium-ion battery is a rechargeable battery that uses the reversible reduction of lithium ions to store energy and is the predominant battery type in many industrial and consumer electronics. The lithium-ion batteries are essential to ensure they operate safely. We conducted an exposure assessment five days after a fire in a battery-testing facility. We assessed some of the potentially hazardous materials after a lithium-ion battery fire. We sampled total suspended particles, hydrogen fluoride, and lithium with real-time monitoring of particulate matter (PM) 1, 2.5, and 10 micrometers (µm). The area sampling results indicated that primary potential hazardous materials such as dust, hydrogen fluoride, and lithium were below the recommended limits suggested by the Korean Ministry of Labor and the American Conference of Governmental Industrial Hygienists Threshold Limit Values. Based on our assessment, workers were allowed to return to work.

Animal Welfare Considerations When Conducting OECD Test Guideline Inhalation and Toxicokinetic Studies for Nanomaterials.

The OECD test guidelines for animal experiments play an important role in evaluating the chemical hazards. Animal tests performed using OECD guidelines, especially when the good laboratory practice (GLP) principle is applied, reduce the duplication of toxicity testing and ensure the best mutual acceptance of data by the OECD's Mutual Acceptance of Data (MAD). The OECD inhalation toxicity test guidelines 412 (28 days) and 413 (90 days) have been revised. These OECD guidelines now reflect the inclusion of nanomaterials and recent scientific and technological developments. In particular, these test guidelines aim to evaluate the bronchoalveolar lavage fluid in the lungs for objective toxicity evaluation, along with the existing subjective histopathological evaluation. For solid particles, the lung burden measurement of particles is required for toxicokinetic studies and, in order to properly perform a toxicokinetic study, two post-exposure observations are recommended. In light of the revised OECD guidelines, we propose a method to reduce the number of animals when testing is conducted for nanomaterials.

The naphthalene state of the science symposium: objectives, organization, structure, and charge.

This report provides a summary of the objectives, organization, structure and charge for the naphthalene state of the science symposium (NS(3)), Monterey, CA, October 9-12, 2006. A 1-day preliminary conference was held followed by a 3-day state of the science symposium covering four topics judged by the Planning Committee to be crucial for developing valid and reliable scientific estimates of low-dose human cancer risk from naphthalene. The Planning Committee reviewed the relevant scientific literature to identify singularly knowledgeable researchers and a pool of scientists qualified to serve as expert panelists. In two cases, independent scientists were commissioned to develop comprehensive reviews of the relevant science in a specific area for which no leading researcher could be identified. Researchers and expert panelists alike were screened for conflicts of interest. All policy issues related to risk assessment practices and risk management were scrupulously excluded. NS(3) was novel in several ways and provides an innovative model for the effective use of peer review to identify scientific uncertainties and propose research strategies for reducing or eliminating them prior to the conduct of risk assessment.

Determination of Thresholds of Radioactive Iodine Uptake Response With Clinical Exposure to Perchlorate: A Pooled Analysis.

OBJECTIVE: To conduct a more robust examination of perchlorate exposure on iodide uptake inhibition (IUI) using pooled data from four clinical studies of perchlorate exposure. METHODS: To establish a response threshold for IUI, data were analyzed using segmented linear regression and benchmark dose (BMD) analysis. RESULTS: Segmented linear regression applied to data for 69 subjects representing nine doses identified a breakpoint corresponding to a change in the slope of the dose-response relationship of 3.0 mg/d perchlorate. The estimated BMD for a 20% decrease in iodine uptake was 2.3 mg/d, with a lower 95% confidence interval limit of 1.6 mg/d. CONCLUSIONS: A threshold dose for IUI from perchlorate exposure of 1.6 to 3.0 mg/d (0.021 to 0.038 mg/kg d) was estimated using two modeling approaches. These estimates are slightly higher than the lowest observed effect level of 0.02 mg/kg d from the Greer Study.

Nanomaterial categorization for assessing risk potential to facilitate regulatory decision-making.

For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future.

Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15.

Urinary nitrate, thiocyanate, and perchlorate and serum thyroid endpoints based on NHANES 2001 to 2002.

OBJECTIVE: To determine, on the basis of iodide uptake inhibition (IUI), whether associations between urinary concentrations of IUI agents (perchlorate, nitrate, and thiocyanate), as total perchlorate equivalent concentration (PEC), and serum thyroid parameters suggest functional thyroid abnormalities. Additional thyroid hormone measures were released to augment the National Health and Examination Survey (NHANES) 2001 to 2002 data set, which we used in this study. METHODS: Enhanced thyroid hormone measures released to augment the National Health and Examination Survey (NHANES) 2001-2002 data set were used in this study. Multiple regression was used to assess the relationships among total thyroxine (TT4), free thyroxine, total triiodothyronine (TT3), free triiodothyronine, and thyroid- stimulating hormone (TSH) and PEC. RESULTS: PEC was weakly and negatively associated with TT4, but not with TSH, TT3, or free hormone. This association with TT4 appears to be dominated by nitrate and thiocyanate. CONCLUSION: No evidence of functional thyroid abnormality (eg., low thyroid hormone coupled with high TSH) was seen with exposure to the combined IUI agents and enhanced estimates of thyroid function.

A multi-stakeholder perspective on the use of alternative test strategies for nanomaterial safety assessment.

There has been a conceptual shift in toxicological studies from describing what happens to explaining how the adverse outcome occurs, thereby enabling a deeper and improved understanding of how biomolecular and mechanistic profiling can inform hazard identification and improve risk assessment. Compared to traditional toxicology methods, which have a heavy reliance on animals, new approaches to generate toxicological data are becoming available for the safety assessment of chemicals, including high-throughput and high-content screening (HTS, HCS). With the emergence of nanotechnology, the exponential increase in the total number of engineered nanomaterials (ENMs) in research, development, and commercialization requires a robust scientific approach to screen ENM safety in humans and the environment rapidly and efficiently. Spurred by the developments in chemical testing, a promising new toxicological paradigm for ENMs is to use alternative test strategies (ATS), which reduce reliance on animal testing through the use of in vitro and in silico methods such as HTS, HCS, and computational modeling. Furthermore, this allows for the comparative analysis of large numbers of ENMs simultaneously and for hazard assessment at various stages of the product development process and overall life cycle. Using carbon nanotubes as a case study, a workshop bringing together national and international leaders from government, industry, and academia was convened at the University of California, Los Angeles, to discuss the utility of ATS for decision-making analyses of ENMs. After lively discussions, a short list of generally shared viewpoints on this topic was generated, including a general view that ATS approaches for ENMs can significantly benefit chemical safety analysis.

Toxicological relevance of pharmaceuticals in drinking water.

Interest in the public health significance of trace levels of pharmaceuticals in potable water is increasing, particularly with regard to the effects of long-term, low-dose exposures. To assess health risks and establish target concentrations for water treatment, human health risk-based screening levels for 15 pharmaceutically active ingredients and four metabolites were compared to concentrations detected at 19 drinking water treatment plants across the United States. Compounds were selected based on rate of use, likelihood of occurrence, and potential for toxicity. Screening levels were established based on animal toxicity data and adverse effects at therapeutic doses, focusing largely on reproductive and developmental toxicity and carcinogenicity. Calculated drinking water equivalent levels (DWELs) ranged from 0.49 microg/L (risperidone) to 20,000 microg/L (naproxen). None of the 10 detected compounds exceeded their DWEL. Ratios of DWELs to maximum detected concentrations ranged from 110 (phenytoin) to 6,000,000 (sulfamethoxazole). Based on this evaluation, adverse health effects from targeted pharmaceuticals occurring in U.S. drinking water are not expected.

Perchlorate and chlorate in dietary supplements and flavor enhancing ingredients.

The oxyhalide anions perchlorate and chlorate were measured in a series of dietary (vitamin and mineral) supplements and flavor enhancing ingredients collected from various commercial vendors in two large US cities. Analyses were conducted using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The limit of detection was based on the mass of supplements and ingredients extracted and ranged from 2 to 15 ng/g for perchlorate and 4 to 30 ng/g for chlorate. Perchlorate and chlorate were detected in 20 and 26, respectively, of the 31 dietary supplements tested, with concentrations ranging from non-detectable to as high as 2400 and 10,300 ng/g, respectively. Based upon the recommended dose provided by each manufacturer for different supplements, the daily oral dose of perchlorate and chlorate could be as high as 18 and 20 microg/day, respectively. The highest level of perchlorate was found in a supplement recommended for pregnant women as a prenatal nutritional supplement. Of the 31 dietary supplements investigated, 12 were specifically marketed for pregnant women and children. Perchlorate and chlorate were also detectable in four products marketed for the enhancement of food flavor. Perchlorate is found naturally in some parts of the world, is present in some natural fertilizers, is used as an oxidizer in solid fuel engines, and has been used at therapeutic doses in humans to treat overactive thyroid glands. Perchlorate has been detected in drinking water, dairy products, some produce and grains, and human breast milk. This is the first report of perchlorate measured in over-the-counter dietary supplements and flavor enhancing ingredients.