By Edward D. Levin, Ph.D., Duke University (firstname.lastname@example.org)
It is commonly assumed that chemical exposures below the minimum dose that cause observed adverse effects indeed have no effect. However, given that the subject under consideration is an integrated organism that uses highly-evolved interacting physiological systems to maintain homeostasis, the “no observed adverse effect” at very low dose chemical exposure is in fact the result of complex responses by the organism to counteract adverse effects of toxicant exposure.
The appearance of adverse effects at higher doses is not the beginning of the effect of the chemical on physiology, but rather the point at which its effects exceed the ability of the organism to accommodate for its actions. These reactive systems protect us from the wide variety of low-level toxicant exposures we encounter daily.
However, the protective mechanisms are not fail-safe. Sometimes these compensatory systems fail and reveal adverse toxic effects at low doses. In other circumstances it is the continued invocation of the compensatory mechanisms that causes adverse consequences in the long run. By understanding the complex systems involved in producing no effect, we can better understand individual differences in susceptibility to toxicity and delayed toxicity. Also, understanding compensatory systems opens new considerations in risk assessment, sources of individual differences in sensitivity, and the development of therapeutic treatments to attenuate the impacts of toxicants or provide therapeutic treatment.
All organisms, including humans, are the products of many millions of years of evolution. Over that period organisms have lived in a variety of environments with differing exposures to chemicals, dietary factors, and environmental stresses. Species that survived evolved multiply redundant and adaptive systems to deal with the changing environment. The maintenance of homeostasis is a hallmark of all living systems. Specific mechanisms for maintaining homeostasis include induction of liver CYP enzymes, scavenging free radicals with glutathione and superoxide dismutase as well as epigenetic responses.
Typically, toxicology investigation starts with clearly observed effects of high-level exposure and proceeds to lower doses that have more modest effects down to the point in the dose-effect function where significant effects of exposure are not seen. However, just because effects of exposure are not seen does not mean that there are not impacts of the toxicant on the organism. There are many cellular and systemic processes that compensate for the impacts of the toxicant and maintain function in the normal range. This constitutes the complex nature of “no effect.”
A better understanding of these processes will improve our appreciation of low dose risks where the compensatory systems may be impaired. Importantly, a better understanding of how compensatory processes normally counteract very low dose toxicant effects can provide leads to therapeutic treatments to prevent or treat toxicant-induced dysfunction in those who do not have sufficient compensatory activity.
Communication is key within and between physiological systems in the integrated organism to provide the dynamic adjustments necessary to accommodate for changes in the environment including chemical exposure. Because of the multiply redundant systems, failure of one line of communication does not necessarily cause an adverse effect when other lines of communication can pick up the slack. However, bad information can be worse than no information at all. In a multiply redundant system, failure of one system leads to another system taking up the role of the failed system.
Less than total failure of a system with low level toxicant exposure can lead to the compromised system providing wrong information, which can lead to dysfunction. As an analogy, a malfunctioning GPS system can misdirect the driver, whereas a nonfunctioning GPS will not have this effect and the driver will be forced to consult an old-fashioned paper map or ask for directions. A severely compromised message will be disregarded as gibberish, whereas a modestly compromised message could give the wrong information; for example, the message “not now” might be partially degraded and incorrectly conveyed as “now.” Such bad messaging may be infrequent but it could become inevitable as the modestly degraded messages continue over an extended period of time or in a great number of individuals. This compromised messaging could cause physiological problems such as in a premature “now” signal to start puberty or deadly problems as in the inappropriate “now” signal starting a cascade of carcinogenic cellular proliferation.
Multiple mechanisms of action could lead to non-monotonic dose effect functions. Low doses may cause simple effects, which might be offset by more complex effects at higher doses. Lower cumulative doses may be the result of intermittency of exposure, which could interfere with appropriate compensation as the level of exposure is rapidly changing. One example of a complex effect is the intermittency of exposure. With continual zero-order kinetic exposure to low level toxicants, the compensatory systems can accommodate and protect us from adverse effects. But when there is intermittent exposure, the compensatory systems can be swamped–not with the degree of simple compensation required to maintain homeostasis, but with the continually shifting requirements for compensation as the toxic stresses on the system are repeatedly shifted.
Perhaps it is not entirely correct to speak of compensation as a process that restores homeostasis, since for many organisms, physiological processes optimally go through dynamic changes throughout the day or with changing environmental or physiological demands (i.e. variable processes of sleep/wakefulness or variable processes of digestion with episodic meals). The concept of homeostasis should be replaced with a “homeodynamic state. ”
If we think about the concept of homeodynamic state, it brings up the possibility that compensatory systems that counteract “sub-threshold” toxicant actions to produce no apparent effect could restrict the homeodynamic range over which the organism can function. That is, low-level toxicant exposure may be compensated for and produce no discernible effect at the time of exposure but could restrict the ability of the organism to adapt to other physiological or environmental fluctuations. This impaired homeodynamism could be regarded as no effect for some latent period until other circumstances within the organism from its environment required a homeodynamic shift that was beyond the capacity of the toxicant-impaired range.
Low dose chemical exposure that does not result in overt phenotypic effects triggers a number of cellular and systemic effects that serve to maintain function within normal bounds of the cell or organism. There are a variety of ways in which toxicant exposure might produce no apparent effect on an organism’s function because compensatory processes of the organism counteract the actions of the toxicant. A low dose of the toxicant may result in a finding of no adverse effect–or even a beneficial effect–because compensatory processes may be overshooting in their efforts to counter toxicity.
To summarize, it is not quite correct to conclude that the dose threshold for a toxicant that does not cause immediate adverse effects is truly a no adverse effect level (NOAEL), when there are endogenous reactions induced by the toxicant that produce the appearance that an organism is functioning normally, at least at the current time. The eventual breakdown of those compensatory systems, or even the effects of the compensation itself, can produce longer-term, delayed adverse effects. In fact, these effects are not really delayed after a silent period; they are the product of a dynamic series of responses to the toxicant, which act to produce the eventual impairment. In short, the nature of a “no effect” level in toxicology is not as simple as it may seem on the surface.