**4. Risk factors for PH-induced LPO**

There are several setbacks to draw from the recent criticisms of PH applications [14, 25, 30]. This is the reason for the suggestions on standardization developments [15, 24, 28, 31]. The latter may help gain insight into their mechanisms as well as potentials for toxicity.

#### **4.1 Dose**

Several PH compounds have been extensively used as a traditional medicine for various therapies [18]. Because of the multifaceted component of PH mixture, several of the published articles showed that manufacturers relied mostly on the documented efficacies of the constituent compounds. There is a lack of specifications for the dose selection of subtherapeutic, therapeutic, and supratherapeutic doses which are used in animal studies, and for animal-to-man dose extrapolations [29]. Till now, there is a lack of formula to relate PH constituents; hence, lack of proper dose extrapolation of a single compound when combined with another may result in the potential mechanistic toxicological effect of the constituent mixture [28, 32]. Several misconceptions about dietary supplements being safe to have increased the number of hospital admissions [14, 17]. Recent studies on the PH dietary supplement popularly known as Cellgevity® (CG) confirmed that this premiere antioxidant supplement formula could act as a pro-oxidant, a substance capable of distorting the antioxidant systems [28]. Studies on the effects of therapeutic and supra-therapeutic doses of CG on reproductive function and biochemical indices in animals demonstrated some detrimental effects. CG is one of the most widely used glutathione supplements that has been considered to be harmless, nevertheless, this general assumption should not be overlooked. It is marketed to salvage for the body glutathione and/or complements its production. D-Ribose and L-Cysteine are the active compounds in CG in addition to the presence of vitamin C, selenium, alphalipoic, broccoli seed extract, curcumin, resveratrol, grape seed extract, quercetin, milk thistle seed extract, cordyceps, black pepper, aloe leaf. Some convergent opinions have highlighted the antioxidant activity of spices and their impact on human health, in particular, to increase reduced glutathione (GSH) concentration [12]. Whereas the presence of GSH improves protein function in a perturbed environment, its roles in modulating hypoxic apoptosis or oxidative stress is of great concern. This has put the faith of current supplement antioxidants in doubt, such as protein supplements and others, which now beg for safety evaluation. Previous studies have reported that dietary supplements are now being used to prevent and treat various diseases [7]. We have now understood that any excess of antioxidants could be detrimental and can result in adverse events and even death. Reports over the past few years have implicated the use of herbs and herbal products to generate reactive oxygen and nitrogen species. Mahwangyounpae-tang (MGT) is another but very popular antioxidant PH consisting of about 22 compounds [32]. Reports on MGT showed that MGT extract was safe for use in asthma at the sub-acute repeated

oral dose levels. However, when the doses were increased per daily in rodents, there were correspondingly increased morphological aberrations and organ histoarchitectural changes characterized by hypertrophy of the heart and tubular necrosis of the kidney [32]. Thus, concerns over the doses of antioxidants when using alone, or with other drugs have arisen (**Table 1**).
