Human & Experimental Toxicology

This article will consider non-linearity and hormesis from the perspectives of risk perception and risk communication. The observations that follow do not come from a scientist or researcher. (For a richer academic treatment of the issue of risk communication and nonlinearity, see BELLE, Vol. 11, Issue 1, 2002). I was for 25 years a journalist on television and in print, focusing on coverage of environmental issues. I then studied and taught risk perception and risk communication at the Harvard School of Public Health. I now independently consult in these areas. From the academic side, I have read a fair amount of the literature that helps explain what I call ‘The Perception Gap,’ the gap between our fears and the facts. And as a journalist and consultant I have witnessed in the real world, people’s relatively greater fear of lesser risks, and relatively lower fear of the risks the scientific data suggest they ought to worry about more. I offer the following perspectives based on those foundations.

In this essay for this issue, David Ropeik empahasizes that it is important to respect the risk perceptions of laypeople. The present commentary examines Ropeik’s suggestion in more detail. First, it clarifies that the notion of ‘respect’ for lat risk perceptions is ambiguous. For example, one could adopt a fairly technocratic perspective (in which policy decisions are based almost exclusively on the risk perceptions of technical experts) while still claiming to respect laypeople. The second section of the commentary rejects such an appraoch; it provides a four-part argument in favor of giving significant weight to the risk perceptions of the public when making policy decisions. It concludes by arguing that these suggestions could be implemented in the hormesis case by adopting the sorts of analytic-deliberative approaches advocated by the National Research Council report Understanding Risk.

We add to the issues raised by Dr David Ropeik’s article Risk Communication and Non-Linearity (forthcoming, BELLE Newsletter, 2008) regarding the thinking about the acceptance of linear and nonlinear (hormetic) dose–response models. We summarize some of the perceptual aspects discussed by Ropeik (2008) and comment on decision-making by the single decision-maker. It seems that the heuristics discussed by Ropeik (2008) are related to those private decision-makers who may not benefit from extensive technical, scientific, and legal advice sufficiently to make well-informed decisions and, perhaps more importantly, may not have the funds for that advice. Dose–response models are intangible, abstract quantities: unlike private goods and services, they are not priced by the market. We suggest a duality between the private and the public decision-maker that in the end may loose its crispness, because it can occur in the same person. Nonetheless, this duality is evident at the analysis phase of decision-making, relative to the decision phase, and thus, provides a convenient way to address the issues addressed by Ropeik (2008). In particular, for at least legal and common sense reasons, the public decision-maker must follow a scientific-analytical causal process – as represented by models of dose–response – to select and justify her choice of one over the other. Whether the final decision as to which model is to be used in regulatory law is a matter that goes beyond the analytical aspects of the choice and is governed by political and other aspects of governance.

The effect of fendiline on cytosolic free Ca²⁺ concentrations ([Ca²⁺]_i) and proliferation has not been explored in human oral cancer cells. This study examined whether fendiline altered Ca²⁺ levels and caused cell death in OC2 human oral cancer cells. [Ca²⁺]_i and cell viability were measured using the fluorescent dyes fura-2 and WST-1, respectively. Fendiline at concentrations above 10 μM increased [Ca²⁺]_i in a concentration-dependent manner. The Ca²⁺ signal was reduced partly by removing extracellular Ca²⁺. The fendiline-induced Ca²⁺ influx was sensitive to blockade of L-type Ca²⁺ channel blockers. In Ca²⁺-free medium, after pretreatment with 50 μM fendiline, 1 μM thapsigargin (an endoplasmic reticulum Ca²⁺ pump inhibitor)-induced [Ca²⁺]_i rises were inhibited; and conversely, thapsigargin pretreatment nearly abolished fendiline-induced [Ca²⁺]_i rises. Inhibition of phospholipase C with 2 μM U73122 did not change fendiline-induced [Ca²⁺]_i rises. At concentrations between 5 and 25 μM, fendiline killed cells in a concentration-dependent manner. The cytotoxic effect of 15 μM fendiline was not reversed by prechelating cytosolic Ca²⁺ with BAPTA/AM. Collectively, in OC2 cells, fendiline induced [Ca²⁺]_i rises by causing Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ influx from L-type Ca²⁺ channels. Furthermore, fendiline-caused cytotoxicity was not via a preceding [Ca²⁺]_i rise.

Inorganic arsenic (iAs) is an environmental toxicant and human carcinogen. The enzymatic methylation of iAs that is catalyzed by arsenic (+3 oxidation state)-methyltransferase (AS3MT) generates reactive methylated intermediates that contribute to the toxic and carcinogenic effects of iAs. We have shown that clonal human urothelial cells (UROtsa/F35) that express rat AS3MT and methylate iAs are more susceptible to acute toxicity of arsenite (iAs^III) than parental UROtsa cells that do not express AS3MT and do not methylate iAs. The current work examines transcriptional changes associated with AS3MT expression and identifies specific categories of genes expressed in UROtsa and UROtsa/F35 cells in response to a 24-h exposure to 1 or 50 μM iAs^III. Here, the expression of 21,073 genes was assessed using Agilent Human 1A(V2) arrays. Venn analysis showed marked concentration-dependent differences between gene expression patterns in UROtsa and UROTsa/F35 cells exposed to iAs^III. Among 134 genes altered by exposure to subtoxic 1 μM iAs^III, only 14 were shared by both cell lines. Exposure to cytotoxic 50 μM iAs^III uniquely altered 1389 genes in UROtsa/F35 and 649 genes in UROtsa cells; 5033 altered genes were associated with the chemical alone. In UROtsa, but not UROtsa/F35 cells exposure to 1 μM iAs^III altered expression of genes associated with cell adhesion. In contrast, expression of genes involved in cell cycle regulation was significantly altered in UROtsa/F35 cells at this exposure level. At 50 μM iAs^III, pathways regulating cell cycle, cell death, transcription, and metabolism were affected in both cell lines. However, only Urotsa/F35 cells showed numerous G-protein and kinase pathway alterations as well as alterations in pathways involved in cell growth and differentiation. These data link the AS3MT-catalyzed methylation of iAs to specific genomic responses in human cells exposed to iAs^III. Further analysis of these responses will help to characterize the role of AS3MT-catalyzed methylation in modulation of iAs^III toxicity.

Arsenic is a classical poison that has been historically used since ancient times for homicidal purposes. More recently, episodes of deliberate or unintentional arsenic self-poisoning have been increasingly reported. We describe here a case of a 77-year old male patient with a history of major depression, who attempted suicide by ingestion of 4 g of arsenic trioxide. The man, a dentist by profession, used arsenic preparations for pulp devitalization. The patient was admitted to our hospital 5 h after arsenic ingestion with nausea and vomiting. Plain radiograph of the abdomen showed radio-opaque material in the stomach and small intestine. Nasogastric lavage, activated charcoal, and chelators were used to remove arsenic. On day 3, endoscopy disclosed the presence of gastritis and superficial ulcers. The patient developed significant anemia (Hb: 8.7 g/dL on day 7) without significant signs of hemolysis. He gradually recovered from anemia within 5 months. The patient did not suffer any adverse outcome in spite of having ingesting 4 g of arsenic, approximately 20 times the lethal dose.