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vegetables have not revealed any cytotoxicity likely due to the more rapid elimination and limiting plasma
concentrations of such compounds.

On the other hand, along a cautionary line, the clinical value of ITCs as chemopreventives and anti-
cancer agents has been tempered by evidence that immune cell functions (T cell and NK cells) may be
[27]
compromised even at low doses (i.e., reducing proliferation of peripheral blood mononuclear cells) . The
real question is whether ITCs access these cell compartments in vivo during ingestion and whether rapid
conjugation (e.g., by GSH) yields derivatives that are less active against immune cells but are still potent
chemopreventives. Since ITCs and metabolites are present in urine and plasma in the nanogram range and
[70]
rapidly eliminated it is conceivable that this very low plasma level alone counters any deleterious effects,
but still permits chemoprevention and anti-tumor effects in a selective uptake and concentration dependent
manner. Certainly, as in vitro experiments are not confounded in this way, does this indicate that a
deleterious effect is yet possible on the immune system? Noteworthy is that ingestion of large amounts of
ITCs has not been found to compromise human health likely due to extensive elimination keeping plasma
[58]
concentrations low . In this context, even low concentrations may in fact be physiologically active since
hormetic effects (see below) and routes of metabolism and tissue accumulation may determine the ultimate
efficacy.

It is important to put such observations in the context of diets where cruciferous plants are consumed on
a regular basis without any obvious negative outcomes. In fact, epidemiological observations vis-à-vis the
MedDiet generally suggests the opposite. Furthermore, plant based diets comprise a very large array of
different phytochemicals that can act additively, synergistically or antagonistically or can protect against
[59]
negative effects . As examples of synergistic effects between ITCs and other polyphenolics in terms of
anti-inflammatory efficacy a number of papers have been published [71,72] . ITCs in combination with anti-
oxidants such as selenium and polyphenolics such as genistein can operate at an epigenetic level [73,74] .
The ITCs AITC and SFN are synergistic for chemoprevention of non-small cell lung carcinoma . More
[75]
examples exist, however this area of research is still not mainstream as many scientists have not yet
appreciated the larger therapeutic efficacy of the vast complexity of functional dietary factors.

Overall, epidemiological observations favor the beneficial side of ingesting cruciferous plants along with
many other unrelated positively influential dietary components (e.g., as found in olive oil). Jaman and
Sayeed reviewed evidence for ellagic acid, sulforaphane, and ursolic acid as possible therapy for breast
[76]
cancer, and although suggestive positive overall, they raised questions about compounds that could
negatively affect both tumor cells and normal cells. As mentioned before, dose is a critical parameter,
and as plasma concentrations of phytochemicals tend to be self limiting in vivo and phytochemicals often
rapidly inactivated or eliminated [58,70] , one needs to consider that most phytochemicals would likely behave
[77]
within the parameters and kinetics of hormesis .

HORMETIC EFFECTS MAY GOVERN THE EFFICACY OF PHYTOCHEMICALS AND LIMIT
TOXICITY
Hormesis, the low dose stress modulatory effect, describes how phytochemicals (including many other
agents) are bimodal in their function often acting positively at a significantly lower dose and acting
[78]
negatively at higher doses [78-81] . There is the idea that early life stressors can lead to resilience in later life ,
and if thought of in the context of dietary factors then early exposure to chemopreventive compounds
[80]
might condition the body for greater resilience or make it refractory to oncogenic stimuli . At another
cellular level, acknowledging that mitochondria are absolutely essential for life, mitohormesis (an adaptive
stress response) defines a biological response where reduction in mitochondrial stress can lead to significant
increments in health and vitality proscribing what is felt to be the anti-aging paradigm [3,82] . Mediators of