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Apr 8, 2013 - To cite this article: Tee L. Guidotti (2013) What is “Toxicologically ... any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever ... Like the difference between “poisoning”.
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What is “Toxicologically Irrelevant”? Tee L. Guidotti

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Archives of Environmental & Occupational Health Published online: 08 Apr 2013.

To cite this article: Tee L. Guidotti (2013) What is “Toxicologically Irrelevant”?, Archives of Environmental & Occupational Health, 68:3, 133-134, DOI: 10.1080/19338244.2012.760361 To link to this article: http://dx.doi.org/10.1080/19338244.2012.760361

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What is “Toxicologically Irrelevant”? Recently a thoughtful colleague in another field who had been reviewing papers in toxicology asked for a clarification. “What,” she asked, “does it mean when a toxicologist writes, ‘toxicologically irrelevant’? Is this is a precise term with a scientific definition, a term of art in law, or a colloquialism? Is this as subjective as it appears?” Good questions! Like the difference between “poisoning” and “toxicity,”1 many terms in toxicology, as in medicine, are not precisely defined in the dictionary. A quick Google search on the specific term “toxicologically irrelevant” yielded over 700 items in which the term is used, often by famous and distinguished toxicologists, but no definition, although the term was often used in defining other terms. Perhaps we can suggest a suitable definition here: A “toxicologically relevant” exposure is an exposure to an agent that may have an effect in another situation, but in the situation under consideration the exposure is too low to produce an effect. For this definition to be valid, it would require exposures to be not only below the threshold of response of every known effect, which is itself a controversial concept,2 but below a concentration at which there would be concern about any effect, known, unknown, subclinical, or disputed. Some toxicologists who enjoy splitting hairs might also apply the term “toxicological irrelevant” to exposures that occur under circumstances in which an effect is virtually impossible. For example, if the agent is not bioavailable, or the agent is in a chemical form (such as Cr(III)) that is essentially nontoxic, there is no intact pathway of exposure, or the host is biologically resistant or lacked susceptibility to the agent. Others might retort that these situations require delineation and should not be dismissed, because an exposure at the same level in a different setting might not be at all irrelevant, even to the same host. Some toxicologists might apply “toxicological irrelevant” to exposures to agents that do not produce an effect. An example of this type of toxicological irrelevance would be exposure to water. There is such a thing as water intoxication but it occurs with a hormonal defect called “syndrome of inappropriate antidiuretic hormone,” almost never as a result of intake alone, although there have been exceptions in

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psychiatric conditions. In these cases, effects are not expected, and if they do occur (for example, drowning) the effect is not mediated by toxicological mechanisms. Some people would put allergic responses in this category (but for water, of course), since they bypass toxicological responses and act by immune mechanisms, which are quite different. If one accepts the controversial concept of hormesis,3 the idea that exposures at low levels provoke stimulatory responses that are different and sometimes opposite to the toxic responses at high exposures to the same chemical, then it may be argued that low exposures within the range of hormesis are not at all “toxicologically irrelevant.” However, this is also true if one believes that the idea of hormesis merely conflates and renames the exposure-response relationships for different outcomes (such as nutritional requirements for trace elements at low levels and toxic effects at high levels), when the effects are not necessarily biologically related. There is another common use of “toxicologically irrelevant,” in official reports and expert opinions in legal cases. In the context of a positive opinion on causation, it is the opposite of a positive opinion expressed “to a reasonable degree of toxicological certainty. . .,” which is the formula toxicologists use where physicians would write “to a reasonable degree of medical certainty” and epidemiologists write “to a reasonable degree of epidemiological certainty.” What do these less than crystal-clear phrases actually mean, other than that lawyers and experts have quirky conventions in the use of language? Well, maybe the language is not so silly after all, even if the formulation does beg the question of what is “reasonable” and does not spell out the standard of certainty. The formulaic phrasing actually means that the opinion is based on evidence comfortably above the “weight of evidence” or “more likely than not” standard in civil litigation. It means that the expert is sure within the limitations and boundaries of the science and knowledge base of toxicology, as a discipline, that the agent caused the effect. In this context, the term “toxicological irrelevance” implies the opposite. It signals that an effect simply would not ever be expected to happen and therefore can be dismissed from further consideration.

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However, before concluding that something is “toxicologically irrelevant,” it is wise to be sure at least to a “reasonable degree of medical/toxicological/epidemiological certainty.”

1. Guidotti TL, Ragain L. Protecting children from toxic exposures: three strategies. Pediatr Clin N Am. 2007;54:227–235. 2. Wennig R. Threshold values in toxicology—useful or not? Forensic Sci Int. 2000;113:323–330. 3. Mushak P. Hormesis and its place in nonmonotonic dose-response relationships: some scientific reality checks. Environ Health Perspect. 2007;115:500–506.

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Tee L. Guidotti Editor-in-Chief Archives of Environmental & Occupational Health

References

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Archives of Environmental & Occupational Health