The vanishing zero revisited: Thresholds in the age of genomics

Abstract

The concept of the Vanishing Zero, which was first discussed 50 years ago in relation to pesticide residues in foods and food crops, focused on the unintended regulatory consequences created by ever-increasing sensitivity and selectivity of analytical methods, in conjunction with the ambiguous wording of legislation meant to protect public health. In the interim, the ability to detect xenobiotics in most substrates has increased from tens of parts per million to parts per trillion or less, challenging our ability to interpret the biological significance of exposures at the lowest detectable levels. As a result the focus of risk assessment, especially for potential carcinogens, has shifted from defining an acceptable level, to extrapolating from the best available analytical results. Analysis of gene expression profiles in exposed target cells using genomic technologies can identify biological pathways induced or repressed by the exposure as a function of dose and time. This treatise explores how toxicogenomic responses at low doses may inform risk assessment and risk management by defining thresholds for cellular responses linked to modes or mechanisms of toxicity at the molecular level.

NanoHPLC-nanoESI+-MS/MS Quantitation of Bis-N7-Guanine DNA–DNA Cross-Links in Tissues of B6C3F1 Mice Exposed to subppm Levels of 1,3-Butadiene

“…Several laboratories, including ours, have previously reported the use of nanospray for sensitive quantitation of DNA adducts. 33–37 …”

“…36 Zarbl et al employed nanoHPLC-nanospray MS to detect and quantitate DNA adducts in bronchial epithelial cells treated with 10 −5 – 10 −8 M concentrations of the N-hydroxy- 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a potent food carcinogen present in overcooked meat. 37 …”

Selenium and mercury molar ratios in saltwater fish from New Jersey: Individual and species variability complicate use in human health fish consumption advisories

“…While it is analytically unlikely to obtain selenium levels below the detection limit of the instrumentation, mercury levels can be below detection limits. This problem occurs much less frequently today than thirty years ago because more sensitive instruments have pushed detection limits downward toward the “vanishing zero” (Zarbl et al 2010). The error involved in using half the detection level is currently relatively small since detection levels in the present study were low (0.0002 ppm in this study), and very few fish were below detection limits for mercury or selenium.…”

Biocompatibility assessment of functionalized magnetic mesoporous silica nanoparticles in human HepaRG cells

“…The first dose with an effect (16 mg/ cm 2 ) can be considered as a 'Lowest Observed Transcriptional Effect Level' (LOTEL). This point is important to underline because, in search of a quantitative method to classify and compare hepatotoxic substances, transcriptomics techniques could be very helpful by providing quantitative responses for toxicity prediction at low doses (Zarbl et al 2010). The dose 16 lg/cm 2 probably triggers the onset of effects that are more clearly observable with a higher dose.…”