Publications by authors named "David Lovell"

Article Synopsis
  • In human health risk assessment, genotoxicity hazards of chemicals typically start with a set of in vitro tests, but these tests don't capture all potential genotoxic endpoints, leading to sometimes contradictory results.
  • Mathematical modeling can improve the interpretation of these tests by accounting for each test's strengths and weaknesses, providing objective predictions with associated uncertainties.
  • A study found that combining a mammalian in vitro clastogenicity test and a gene mutation test offers strong evidence for genotoxic hazard assessment, but the bacterial reverse mutation (Ames) test alone can still provide useful evidence when no other data is available.
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The Cramer classification scheme has emerged as one of the most extensively-adopted predictive toxicology tools, owing in part to its employment for chemical categorisation within threshold of toxicological concern evaluation. The characteristics of several of its rules have contributed to inconsistencies with respect to degree of hazard attributed to common (particularly food-relevant) substances. This investigation examines these discrepancies, and their origins, raising awareness of such issues amongst users seeking to apply and/or adapt the rule-set.

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Background: Few methods are available for transparently combining different evidence streams for chemical risk assessment to reach an integrated conclusion on the probability of causation. Hence, the UK Committees on Toxicity (COT) and on Carcinogenicity (COC) have reviewed current practice and developed guidance on how to achieve this in a transparent manner, using graphical visualisation.

Methods/approach: All lines of evidence, including toxicological, epidemiological, new approach methodologies, and mode of action should be considered, taking account of their strengths/weaknesses in their relative weighting towards a conclusion on the probability of causation.

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Exposure levels without appreciable human health risk may be determined by dividing a point of departure on a dose-response curve (e.g., benchmark dose) by a composite adjustment factor (AF).

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Quantitative risk assessments of chemicals are routinely performed using in vivo data from rodents; however, there is growing recognition that non-animal approaches can be human-relevant alternatives. There is an urgent need to build confidence in non-animal alternatives given the international support to reduce the use of animals in toxicity testing where possible. In order for scientists and risk assessors to prepare for this paradigm shift in toxicity assessment, standardization and consensus on in vitro testing strategies and data interpretation will need to be established.

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Cells within the tumour microenvironment (TME) can impact tumour development and influence treatment response. Computational approaches have been developed to deconvolve the TME from bulk RNA-seq. Using scRNA-seq profiling from breast tumours we simulate thousands of bulk mixtures, representing tumour purities and cell lineages, to compare the performance of nine TME deconvolution methods (BayesPrism, Scaden, CIBERSORTx, MuSiC, DWLS, hspe, CPM, Bisque, and EPIC).

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Historical negative control data (HCD) have played an increasingly important role in interpreting the results of genotoxicity tests. In particular, Organisation for Economic Co-operation and Development (OECD) genetic toxicology test guidelines recommend comparing responses produced by exposure to test substances with the distribution of HCD as one of three criteria for evaluating and interpreting study results (referred to herein as "Criterion C"). Because of the potential for inconsistency in how HCD are acquired, maintained, described, and used to interpret genotoxicity testing results, a workgroup of the International Workshops for Genotoxicity Testing was convened to provide recommendations on this crucial topic.

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Disaster victim identification (DVI) entails a protracted process of evidence collection and data matching to reconcile physical remains with victim identity. Technology is critical to DVI by enabling the linkage of physical evidence to information. However, labelling physical remains and collecting data at the scene are dominated by low-technology paper-based practices.

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It is often assumed that genotoxic substances will be detected more easily by using in vitro rather than in vivo genotoxicity tests since higher concentrations, more cytotoxicity and static exposures can be achieved. However, there is a paucity of data demonstrating whether genotoxic substances are detected at lower concentrations in cell culture in vitro than can be reached in the blood of animals treated in vivo. To investigate this issue, we compared the lowest concentration required for induction of chromosomal damage in vitro (lowest observed effective concentration, or LOEC) with the concentration of the test substance in blood at the lowest dose required for biologically relevant induction of micronuclei in vivo (lowest observed effective dose, or LOED).

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In this article the importance of study design will be emphasized, statistical methods for analysing the data are described and some of the implications of these method are discussed. How these issues relate to the use of SpIN and SnOUT rules are reviewed.

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This article discusses issues associated with the design and interpretation of biomarker studies, points to various guidelines and lists points to look out for in assessing studies.

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Diagnostic statistics such as sensitivity and specificity are widely used in the assessment of biomarkers. Interpretation of these and other statistics derived from a 2 × 2 table can be complex. The properties of the commonly used statistics are discussed.

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We present a novel approach to the Metagenomic Geolocation Challenge based on random projection of the sample reads from each location. This approach explores the direct use of k-mer composition to characterise samples so that we can avoid the computationally demanding step of aligning reads to available microbial reference sequences. Each variable-length read is converted into a fixed-length, k-mer-based read signature.

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The rodent Pig-a assay is a flow cytometric, phenotype-based method used to measure in vivo somatic cell mutation. An Organization for Economic Co-operation and Development (OECD) test guideline is currently being developed to support routine use of the assay for regulatory purposes (OECD project number 4.93).

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Thanks to sequencing technology, modern molecular bioscience datasets are often compositions of counts, e.g. counts of amplicons, mRNAs, etc.

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The etiology of distal site cancers in inflammatory bowel disease (IBD) is not well understood and requires further study. We investigated whether pediatric IBD patients' blood cells exhibit elevated levels of genomic damage by measuring the frequency of mutant phenotype (CD59-/CD55-) reticulocytes (MUT RET) as a reporter of PIG-A mutation, and the frequency of micronucleated reticulocytes (MN-RET) as an indicator of chromosomal damage. IBD patients (n = 18 new-onset disease, 46 established disease) were compared to age-matched controls (constipation or irritable bowel syndrome patients from the same clinic, n = 30) and young healthy adults age 19-24 (n = 25).

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We previously described flow cytometry-based methods for scoring the incidence of micronucleated reticulocytes (MN-RET) and PIG-A mutant phenotype reticulocytes (MUT RET) in rodent and human blood samples. The current report describes important methodological improvements for human blood analyses, including immunomagnetic enrichment of CD71-positive reticulocytes prior to MN-RET scoring, and procedures for storing frozen blood for later PIG-A analysis. Technical replicate variability in MN-RET and MUT RET frequencies based on blood specimens from 14 subjects, intra-subject variability based on serial blood draws from 6 subjects, and inter-subject variation based on up to 344 subjects age 0 to 73 years were quantified.

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To specify symptoms and measure prevalence of psychological distress among incarcerated people in long-term solitary confinement. We gathered data via semistructured, in-depth interviews; Brief Psychiatric Rating Scale (BPRS) assessments; and systematic reviews of medical and disciplinary files for 106 randomly selected people in solitary confinement in the Washington State Department of Corrections in 2017. We performed 1-year follow-up interviews and BPRS assessments with 80 of these incarcerated people, and we present the results of our qualitative content analysis and descriptive statistics.

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The Null Hypothesis Significance Testing (NHST) paradigm is increasingly criticized. Estimation approaches such as point estimates and confidence intervals, while having limitations, provide better descriptions of results than P-values and statements about significance levels. Their use is supported by many statisticians.

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The working group reached complete or majority agreement on many issues. Results from TGR and in vivo comet assays for 91 chemicals showed they have similar ability to detect in vivo genotoxicity per se with bacterial mutagens and Ames-positive carcinogens. TGR and comet assay results were not significantly different when compared with IARC Group 1, 2 A, and unclassified carcinogens.

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A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset.

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A database of the micronuclei counts was built up for historical negative control data from human lymphocyte in vitro micronuclei tests (MnVit) carried out in 8 laboratories with experience of the method. The mean incidence of micronucleated cells (mnt)/1000 cells ranged from 2.2/1000 to 15.

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The market for smartphones, smartwatches, and wearable devices is booming. In recent years, individuals and researchers have used these devices as additional tools to monitor and track sleep, physical activity, and behavior. Their use in sleep research and clinical applications could address the difficulties in scaling up studies that rely on polysomnography, the gold-standard.

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The recent revisions of the Organisation for Economic Co-operation and Development (OECD) genetic toxicology test guidelines emphasize the importance of historical negative controls both for data quality and interpretation. The goal of a HESI Genetic Toxicology Technical Committee (GTTC) workgroup was to collect data from participating laboratories and to conduct a statistical analysis to understand and publish the range of values that are normally seen in experienced laboratories using TK6 cells to conduct the in vitro micronucleus assay. Data from negative control samples from in vitro micronucleus assays using TK6 cells from 13 laboratories were collected using a standard collection form.

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