US National Toxicology Program Research Articles

Water fluoridation between public health and public law: an assessment of regulations across countries and their preventive medicine implications.

Among health professionals and health policymakers concern is growing as to the difficulty of balancing the prevention of dental caries through cost-effective interventions and the need to limit unnecessary exposure of the population, and especially children, to environmental chemicals. In this respect, the use of water fluoridation to prevent tooth decay epitomizes the dilemma by raising questions relevant to both public health and public law, ranging from the balance of public health and medical self-determination, the division of powers between local or national authorities over water fluoridation, and the need to avoid the adverse effects of socioeconomic inequalities as well as both under- and over-exposure. We carried out a narrative review by searching the relevant literature about the laws and rules related to drinking water fluoridation at the community level in the US, UK, and Europe, in order to discuss how the issue is handled from both a public health and public law perspective. Sources of data for this review were the biomedical and legal literature retrieved by searching online databases, and websites of public health and legal institutions. We found that water fluoridation is still largely adopted throughout the US, while in the UK and particularly in the European Union only a minor part of the population is subject to it. In addition, the recommended and maximum allowed amounts of fluoride in drinking water are being adapted to the public health recommendations and the new regulations, within an evolving evaluation of the epidemiologic evidence and the risk assessment currently in progress by two major regulatory agencies, the US National Toxicology Program - NTP and the European Food Safety Authority - EFSA. Under a comparative public law perspective, the three investigated legislations are facing a reassessment of their policies and regulations, to allow for effective and safe public health measures in the field of water fluoridation and more generally for a preferred use of topical fluoride for caries prevention. A consistent trend across these legislations is the choice to centralize at the national level regulatory and management issues related to water fluoridation, and to carefully balance benefits for dental caries prevention in children and the potential risks of systemic overexposure associated with excess fluoride intake, by promptly responding to the evolving indications by the scientific community and the public health professionals.

Comparison of transcriptome alterations induced by pendimethalin or its commercial formulation Stomp Aqua in human MCF-7, MCF-10 A and MCF-12 A mammary epithelial cells

ObjectiveThe toxicology of herbicides, which are currently in use is under-explored. One highly used but under investigated herbicide is pendimethalin. Here we mined high-throughput data from the US National Toxicology Program (NTP) to identify whether pendimethalin possesses an estrogenic capability in human cells. We also evaluated effects of pendimethalin and its reference commercial formulated herbicide Stomp Aqua on the transcriptome profile of three human mammary epithelial cell lines, cancerous MCF-7 and non-cancerous MCF-10 A and MCF-12 A to see whether this compound could have endocrine disrupting effects and if co-formulants present in the commercial formulation could amplify its toxicity.ResultsThe data mined from the US NTP database suggests that pendimethalin activates estrogen receptors at a concentration of approximately 10?M. MCF-7, MCF-10A and MCF-12A cells were exposed to 10 ?M pendimethalin and Stomp Aqua at an equivalent concentration. Transcriptome analysis showed changes in gene expression patterns implying that pendimethalin affected ubiquitin-mediated proteolysis and the function of the spliceosome. The formulated pendimethalin product Stomp Aqua gave comparable effects suggesting pendimethalin was responsible for the observed transcriptome alterations. Given the lack of information on the exposure to this pesticide, our study prompts the need for biomonitoring studies, especially under occupational use scenarios, to understand if low level exposure to pendimethalin could have endocrine disrupting effects on populations exposed to this compound. A deeper understanding of the exposure and mechanisms of action of this endocrine-disrupting pesticide is needed.

Profiling mechanisms that drive acute oral toxicity in mammals and its prediction via machine learning.

We present a mechanistic machine-learning quantitative structure-activity relationship (QSAR) model to predict mammalian acute oral toxicity. We trained our model using a rat acute toxicity database compiled by the US National Toxicology Program. We profiled the database using new and published profilers and identified the most plausible mechanisms that drive high acute toxicity (LD50 ≤ 50 mg/kg; GHS categories 1 or 2). Our QSAR model assigns primary mechanisms to compounds, followed by predicting their acute oral LD50 using a random-forest machine-learning model. These predictions were further refined based on structural and mechanistic read-across to substances within the training set. Our model is optimized for sensitivity and aims to minimize the likelihood of underpredicting the toxicity of assessed compounds. It displays high sensitivity (76.1% or 76.6% for compounds in GHS 1-2 or GHS 1-3 categories, respectively), coupled with ≥73.7% balanced accuracy. We further demonstrate the utility of undertaking a mechanistic approach when predicting the toxicity of compounds acting via a rare mode of action (MOA) (aconitase inhibition). The mechanistic profilers and framework of our QSAR model are route- and toxicity endpoint-agnostic, allowing for future applications to other endpoints and routes of administration. Furthermore, we present a preliminary exploration of the potential role of metabolic clearance in acute toxicity. To the best of our knowledge, this effort represents the first accurate mechanistic QSAR model for acute oral toxicity that combines machine learning with MOA assignment, while also seeking to minimize underprediction of more highly potent substances.

Abstract C107: Racial differences in associations between chemical exposures and cancer-specific mortality

Abstract We lack knowledge of environmental drivers (e.g. chemical exposures) of cancer mortality, which is most often due to the development of metastatic disease. Thus, there is a need to identify associations between chemical exposures and cancer mortality to help prioritize chemicals for further toxicological and epidemiological studies. We aimed to characterize how the associations between chemical biomarker levels and cancer-specific mortality differ by race/ethnicity to identify which concentrations are associated with increased risk for cancer death for each race/ethnicity. We studied 241 toxicant biomarkers in 35,132 participants sampled from the US CDC National Health and Nutrition Examination Survey 1999-2014. We deployed a series of Cox proportional hazard models with mortality status for cancer and time to death as the outcome variables and the chemical concentrations as the main predictor for each race/ethnicity. We adjusted for covariates such as age, sex, poverty income ratio, smoking, and comorbidity. For non-Hispanic Black participants, we found that an increase of one standard deviation in methyl paraben, a compound used in personal care product, is associated with a 60% increase in risk for cancer death (FDR-adjusted p-value = 4.22E-04). In addition, increased levels of lead and cadmium are associated with increased cancer mortality risk. The hazard ratio for an increase in one standard deviation of lead is 1.21 (FDR-adjusted value = 7.16E-06) in non-Hispanic Blacks and is 1.14 (FDR-adjusted p-value = 5.71E-04) in non-Hispanic Whites. The hazard ratio for cadmium is 1.37 (FDR-adjusted value = 3.06E-06) in non-Hispanic Blacks and is 1.26 (FDR-adjusted p-value = 9.23E-07) in non-Hispanic Whites. According to the International Agency for Research on Cancer (IARC) and the US National Toxicology Program (NTP), cadmium is a known carcinogen, and lead is a probable carcinogen. Methyl paraben is not even listed as a probable or known carcinogen but shows higher cancer mortality risk compared to those of lead and cadmium. In addition, the effect of methyl paraben on cancer have not been well studied. Thus, our methodology can help identify chemical contributors to cancer mortality for further mechanistic evaluation. Citation Format: Vy K. Nguyen, Chirag J. Patel, Olivier Jolliet, Justin Colacino. Racial differences in associations between chemical exposures and cancer-specific mortality [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C107.

Monte-Carlo Based Numerical Dosimetry in Reverberation Chamber Exposure Systems Employed for in-Vivo Rodent Bioassays

A Monte-Carlo based computational approach for the statistical characterization of the whole-body specific absorption rate (wbSAR) variability in large cohorts of rodents exposed to radio-frequency (RF) energy in reverberation chambers (RCs) is applied to adult male rat exposures illustrative of those in a US National Toxicology Program (NTP) cancer bioassay. A large number of 3D electromagnetic field realizations fulfilling Rayleigh fading properties were generated within an electrically-large volume representative of an ideal RC, yielding granular wbSAR distributions for an ensemble of 96 homogeneous rodent models with random mass distribution, postures, positions and orientations. Two case studies were addressed: a “momentary exposure” with each rat fixed in posture, position and orientation, and a “day-long exposure” in which the position, orientation and posture were varied randomly for each subsequent Rayleigh field realization. Over 500 and 2500 field realizations or “snapshots”, respectively, the rats’ instantaneous wbSARs, as well as their individual time-averaged wbSARs, were found to be well fit by lognormal distributions. The large variability in instantaneous wbSARs in the cohort was due in part to the inherent Rayleigh field variability in RCs (70-80%) and in part to weight, posture and position variations (20-30%), while the effect of cage location was found to be small over day-long exposures. Averaging the exposure over field realizations substantially reduces the range of wbSARs in the cohort. Hence, when RF-induced thermal effects are studied, the relevant exposure metric (wbSAR averaged over appropriate times) features a narrower range than instantaneous wbSAR, which is the relevant metric in studies dealing with non-thermal effects. Compared to previous studies, the present approach was found to be computationally more efficient enabling thus a Monte-Carlo analysis by varying concurrently the incident field and the animals posture, position, and orientation. In practice, it can inform the choice of wbSAR targets in rodent bioassay, allowing to identify possible dose-effect trends while avoiding undue thermal stress.

Exposure, risk and predictors of hexabromocyclododecane and Tetrabromobisphenol-A in house dust from urban, rural and E-waste dismantling sites in Thailand.

In this study, for the first time, we determined concentrations of hexabromocyclododecane (HBCDD) and tetrabromobisphenol-A (TBBPA) in house dust and estimated human exposure to these substances in houses located in an e-waste dismantling site and in urban and rural residential areas of Thailand. The median HBCDD concentration in urban residential houses (2.10ngg-1) was similar to that in houses in an e-waste dismantling site (2.05ngg-1, p>0.05) and slightly higher than that in rural residential houses (1.11ngg-1, p>0.05). In contrast, significantly higher TBBPA concentrations were present in house dust from an e-waste dismantling site (median=720ngg-1; range=44-2300ngg-1) compared to those in urban (68.6ngg-1; 3.5-300ngg-1, p<0.001) and rural residential areas (17ngg-1; 2.0-201ngg-1, p<0.001). TBBPA concentrations increased with the increasing presence of electronic devices and a decreasing distance to the e-waste dismantling site. These results suggest that e-waste dismantling activities may contribute to TBBPA contamination of house dust. The median estimated daily intake (EDI) of HBCDD and TBBPA through dust ingestion for toddlers exceeded that for children and adults. However, EDI values for HBCDD and TBBPA from all age groups were below the oral reference dose guideline value suggested by the US National Research Council and National Toxicology Program (NTP).

Quantification of Exposure Level in a Reverberation Chamber for a Large-Scale Animal Study

The US National Toxicology Program (NTP) conducted a long-term carcinogenic and toxicity study with small animals on the effects of mobile phone radiation at 900 MHz and 1900 MHz, respectively, and showed an increase in incidence of malignant schwannomas in the heart of male rats at very higher exposure levels. To verify and clarify the NTP study results, Japan and Korea are conducting a joint study using the same reverberation chamber type exposure system as in the NTP study. The purpose of this paper is to derive a quantitative relationship between the electric field strength in the reverberation chamber and the exposure level, i.e., the mean whole-body averaged specific absorption rate (WBA <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\_$</tex-math></inline-formula> SAR) of rats based on a large-scale finite difference time domain (FDTD) simulation. First, two FDTD simulation methods, one with a single plane wave incidence and the other with simultaneous plane wave incidence, were compared, and then the former method was adopted for convenience and saving calculation time. The derived quantitative relationship between the WBA <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\_$</tex-math></inline-formula> SAR and the electric field strength required to achieve the WBA <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\_$</tex-math></inline-formula> SAR consists of a one-dimensional approximation model which considers only the body mass of rats and a two-dimensional approximation model which considers not only the body mass but also the number of rats. The two approximation models cover the entire two-year exposure period, and the exposure level in the two-year long-term exposure experiment is being well controlled. Moreover, unlike dosimetry in the NTP study, an uncertainty analysis of numerical dosimetry was performed in more details, and the combined standard uncertainty in the WBA <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\_$</tex-math></inline-formula> SAR was found to be 16.1 <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\%$</tex-math></inline-formula> .

Systematic Methods to Select and Review Epidemiological Literature on the Health Effects of Long-term Exposure to TRAP

BACKGROUND AND AIM: The health effects of traffic-related air pollution (TRAP) continue to be of important public health interest. Following its well-cited 2010 critical review, HEI appointed a new expert Panel to review the literature on the health effects of long-term exposure to TRAP. METHODS: The Panel followed a systematic protocol they published in Prospero to search the literature, assess study quality, summarize results, and reach conclusions about the body of evidence. An extensive search was conducted of literature published between January 1980 and July 2019 on selected health outcomes (all-cause and cause-specific mortality, respiratory effects, cardiometabolic effects, and adverse birth outcomes). The Panel considered studies both within and outside the near-road environment because traffic contributes to ambient air pollution at neighborhood and urban scales. They developed a framework of exposure to TRAP to guide transparent selection and evaluation of epidemiological studies. Criteria including the pollutant considered, spatial scale, and exposure assessment methods were used to identify studies in which the exposure contrasts were related primarily to traffic emissions. RESULTS:Meta-analyses were performed in cases where three or more studies were identified for the same exposure and health outcome. Conclusions were based on a modified US National Toxicology Program’s Office of Health Assessment and Translation (OHAT) approach and a narrative assessment. The two approaches were considered equally valuable in the Special Report, reflecting the complex issues in determining the level of confidence. CONCLUSIONS:The review is now well underway, and the methods along with lessons learned during their application will be presented. The systematic review will undergo peer-review, and publication is aimed for late 2021. The new review will be an authoritative update of HEI’s most-cited report for use by researchers and policymakers. KEYWORDS: traffic-related air pollution, systematic review, birth outcomes, cardiometabolic effects, respiratory effects, mortality

Occupational exposure to antimony trioxide: a risk assessment

ObjectivesThe US National Toxicology Program (NTP) recently recommended in its Report on Carcinogens Monograph for Antimony Trioxide that antimony trioxide be listed as ‘reasonably anticipated to be a human carcinogen’...

Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools

BackgroundSystematic reviews are increasingly prevalent in environmental health due to their ability to synthesize evidence while reducing bias. Different systematic review methods have been developed by the US National Toxicology Program’s Office of Health Assessment and Translation (OHAT), the US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS), and by the US EPA under the Toxic Substances Control Act (TSCA), including the approach to assess risk of bias (ROB), one of the most vital steps which is used to evaluate internal validity of the studies. Our objective was to compare the performance of three tools (OHAT, IRIS, TSCA) in assessing ROB.MethodsWe selected a systematic review on polybrominated diphenyl ethers and intelligence quotient and/or attention deficit hyperactivity disorder because it had been endorsed by the National Academy of Sciences. Two reviewers followed verbatim instructions from the tools and independently applied each tool to assess ROB in 15 studies previously identified. We documented the time to apply each tool and the impact the ROB ratings for each tool had on the final rating of the quality of the overall body of evidence.ResultsThe time to complete the ROB assessments varied widely (mean = 20, 32, and 40 min per study for the OHAT, IRIS, and TSCA tools, respectively). All studies were rated overall “low” or “uninformative” using IRIS, due to “deficient” or “critically deficient” ratings in one or two domains. Similarly, all studies were rated “unacceptable” using the TSCA tool because of one “unacceptable” rating in a metric related to statistical power. Approximately half of the studies had “low” or “probably low ROB” ratings across all domains with the OHAT and Navigation Guide tools.ConclusionsTools that use overall ROB or study quality ratings, such as IRIS and TSCA, may reduce the available evidence to assess the harms of environmental exposures by erroneously excluding studies, which leads to inaccurate conclusions about the quality of the body of evidence. We recommend using ROB tools that circumvents these issues, such as OHAT and Navigation Guide.Systematic review registrationThis review has not been registered as it is not a systematic review.

Self-augmenting Knowledge Base for Informed Decision Making With Biomedical Applications in Cancer Diagnosis

Fuzzy sets methodology to automatically generate knowledge base for informed decision making is proposed. As a proof of concept it has initially been applied to generate regulatory/health/environmental guidance rules for textile and apparel companies. Subsequently, the system will be augmented to incorporate additional consumer goods, and down the road, after some modifications, could be utilized as a much needed health care disruptor tool in personalized medicine for both patients and clinicians. The apparel category provides for a diverse set of mandatory regulations and some voluntary standards. Mandatory requirements such as CPSIA, FTC for Care and Textile labelling, in addition to AATCC requirements for colourfastness and formaldehyde were taken into consideration. Initial focus was on carcinogenic dyes and pigments. Databases from the International Agency for Research on Cancer (IARC), the US National Toxicology Program (NTP) are to be incorporated, in conjunction with computational intelligence, to identify potential toxins or carcinogens present in the industrial process or the final product, thus alerting manufactures and consumers through a user-friendly interface. This capability can be quickly developed and validated using modern software product development approaches incorporating Design Thinking, Agile Development with Scrum, and Business Model Generation to get this to market where key benefits can be derived

Risk Assessment of Coumarin Intake in the Norwegian Population

Risk Assessment of Coumarin Intake in the Norwegian Population

The Contribution of In Vivo Mammalian Studies to the Knowledge of Adverse Effects of Radiofrequency Radiation on Human Health.

The proliferation of cellular antennas and other radiofrequency radiation (RFR) generating devices of the last decades has led to more and more concerns about the potential health effects from RFR exposure. Since the 2011 classification as a possible carcinogen by the International Agency for Research on Cancer (IARC), more experimental studies have been published that support a causal association between RFR exposure and health hazards. As regard cancer risk, two long-term experimental studies have been recently published by the US National Toxicology Program (NTP) and the Italian Ramazzini Institute (RI). Despite important experimental differences, both studies found statistically significant increases in the development of the same type of very rare glial malignant tumors. In addition to carcinogenicity, reproductive organs might be particularly exposed, as well as sensitive to RFR. In this work, we reviewed the currently available evidence from in vivo studies on carcinogenicity and reproductive toxicity studies in order to summarize the contribution of experimental research to the prevention of the adverse effects of RFR on human health.

Short-chain and long-chain PFAS show similar toxicity

Short-chain perfluoroalkyl sulfonates and perfluoroalkyl carboxylates adversely affect rat livers and thyroid hormones just like their long-chain homologues do, the US National Toxicology Program says. But causing those effects requires higher doses of the short-chain versions of these environmentally persistent synthetic chemicals. That’s because the short-chain compounds generally have shorter half-lives in rodents than the longer-chain ones do, explains NTP Director Linda Birnbaum. These findings could have implications for establishing cleanup standards for drinking water and soil contaminated with these and other per- and polyfluoroalkyl substances. The perfluoroalkyl sulfonates are considered short chain if they have five or fewer carbons, while the carboxylates are considered short chain if they have seven or fewer carbons. NTP drew its conclusions on the basis of two 28-day studies in laboratory rats. One examined the effects of two short-chain chemicals—perfluorobutane sulfonic acid and perfluoro...

C&amp;EN talks with Brian Berridge, toxicology research innovator

After more than 40 years of evaluating the hazards of chemicals by testing animals to extrapolate human health effects, the US National Toxicology Program is shifting gears. Under the direction of Associate Director Brian Berridge, the program is embracing innovative technologies such as artificial intelligence and in vitro human cell systems in hopes of making chemical hazard assessments more relevant to people. The NTP is also flipping its process for chemical hazard assessment upside down. Rather than starting with individual chemicals or classes of chemicals and looking for their health hazards, the program is looking into whether particular diseases that have a big impact on public health have chemical origins. Berridge joined the NTP in January 2018, after more than a decade working for the pharmaceutical company GlaxoSmithKline. There, he was the first to lead a group examining the role of animals in drug development. The group was started “with

Derivation of an occupational exposure limit for diacetyl using dose-response data from a chronic animal inhalation exposure study.

Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8hour time-weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC10 ) and the associated 95% lower confidence bound (BMCL10 ), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics-physiologically based pharmacokinetic (CFD-PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8hour TWA OEL values with a range of 0.16-0.70ppm. The recommended 8hour TWA OEL for diacetyl vapor of 0.2ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health-protective.

Reflections on the progress towards non-animal methods for acute toxicity testing of chemicals

The acute toxicity ‘six-pack’ is a suite of tests for hazard identification and risk assessment, primarily conducted for the classification and labelling of industrial chemicals and agrochemicals. The ‘six-pack’ is designed to provide information on health hazards likely to arise from short-term exposure to chemicals via inhalation, oral and dermal routes, including the potential for eye and skin irritation/corrosion and skin sensitization. The component tests of the ‘six-pack’ currently rely heavily on the use of experimental animals. In 2017, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), together with the European Union Reference Laboratory for Alternatives to Animal Testing (EURL-ECVAM), and the US National Toxicology Program (NTP) Centre for the Evaluation of Alternative Methods (NICEATM) held a workshop entitled ‘Towards Global Elimination of the Acute Toxicity ‘Six-Pack’’ to explore opportunities to use alternative (non-animal) methods for hazard identification and classification without compromising human or environmental safety.The Workshop included scientists from regulatory agencies and industrial organisations worldwide, and sought to gain a more detailed understanding of the barriers to the adoption of suitable animal-free alternatives at an international level. Among the issues addressed were: the recurring theme of validation and scientific credibility, as well as the need for international standards, an understanding of the limitations of each new/alternative method and characterisation against the variability of current animal methods. The practicality and cost of new tests was also an important consideration. However, the need for mutual acceptance, and global harmonization of requirements were thought to be the major hurdle to overcome to realise a vision of the eventual complete elimination of the current, animal test-based, acute toxicity ‘six-pack’.

Assessment of Particle Oxidative Potential as an Air Pollution Exposure Metric: A Systematic Review

Ambient particulate air pollution is linked to numerous acute and chronic health outcomes. The standard approach to measuring particulate exposure has been to estimate particle mass concentration. New measures account for oxidative potential, the ability of particles to cause oxidative stress in the body. There has been no systematic comparison of particulate air pollution exposure assessment methods between those that incorporate oxidative potential and those that do not. The aim of this review is to determine if associations between particulate air pollution exposure and health outcomes are stronger when oxidative potential is used as the exposure metric, in comparison to particle mass concentration. The databases Medline and Embase were searched from inception to 28 March 2018 for studies that reported an association between particulate air pollution exposure and a health outcome in a human population, and in which exposure was measured by both particle mass concentration and oxidative potential. Study quality was assessed using a US National Toxicology Program instrument. We identified 18 publications meeting the selection criteria. The most common oxidative potential assay was antioxidant depletion in synthetic respiratory tract lining fluid, used in 12 articles. The rate of consumption of dithiothreitol was also frequently used as an oxidative potential assay and appeared in 5 studies. The dithiothreitol assay most consistently produced stronger effect estimates, as 10/14 endpoints showed higher point estimates of associations compared to particle mass concentration estimates. Other assays showed mixed results. To date there is no consistent evidence that oxidative potential is more strongly associated with health outcomes than particle mass concentrations; however, these assays do have the advantage of not treating all particles as equally harmful and further work should explore which specific assays are most relevant to evaluating air pollution health risks.

Clinical and genomic safety of treatment with Ginkgo biloba L. leaf extract (IDN 5933/Ginkgoselect\xaePlus) in elderly: a randomised placebo-controlled clinical trial [GiBiEx

BackgroundNumerous health benefits have been attributed to the Ginkgo biloba leaf extract (GBLE), one of the most extensively used phytopharmaceutical drugs worldwide. Recently, concerns of the safety of the extract have been raised after a report from US National Toxicology Program (NTP) claimed high doses of GBLE increased liver and thyroid cancer incidence in mice and rats. A safety study has been designed to assess, in a population of elderly residents in nursing homes, clinical and genomic risks associated to GBLE treatment.MethodsGiBiEx is a multicentre randomized clinical trial, placebo controlled, double blinded, which compared subjects randomized to twice-daily doses of either 120-mg of IDN 5933 (also known as Ginkgoselect®Plus) or to placebo for a 6-months period. IDN 5933 is extracted from dried leaves and contains 24.3% flavone glycosides and 6.1% of terpene lactones (2.9% bilobalide, 1.38% ginkgolide A, 0.66% ginkgolide B, 1.12% ginkgolide C) as determined by HPLC. The study was completed by 47 subjects, 20 in the placebo group and 27 in the treatment group. Clinical (adverse clinical effect and liver injury) and genomic (micronucleus frequency, comet assay, c-myc, p53, and ctnnb1 expression profile in lymphocytes) endpoints were assessed at the start and at the end of the study.ResultsNo adverse clinical effects or increase of liver injury markers were reported in the treatment group. The frequency of micronuclei [Mean Ratio (MR) = 1.01, 95% Confidence Intervals (95% CI) 0.86–1.18), and DNA breaks (comet assay) (MR = 0.91; 95% CI 0.58–1.43), did not differ in the two study groups. No significant difference was found in the expression profile of the three genes investigated.ConclusionsNone of the markers investigated revealed a higher risk in the treatment group, supporting the safety of IDN 5933 at doses prescribed and for duration of six months.Trial registrationClinicalTrials.gov Identifier: NCT03004508, December 20, 2016. Trial retrospectively registered.

Cadmium in soybeans and the relevance to human exposure

Introduction Cadmium is considered a human carcinogen by the International Agency for Research on Cancer(IARC,1993)and the US National Toxicology Program(NTP,1997).Cadmium contamination of food crops is a persistent issue for both the agricultural industry as well as consumers.This is an issue for agriculture because cadmium can be present in soils naturally or as a result of industrial processes and can contaminate foods that are consumed by humans.Industrial