The Ayurvedic drug Mahayograj guggulu manufactured as per the classical method was tested for its content of heavy metals and chronic toxicity.
As compared with the heavy metal contents reported by Saper et al
] in the same batch of the drug, we found different amounts of heavy metals (lead: 37 µg/g as against 25.8 µg/g in our study; mercury: 22.8 µg/g as against 0.07 µg/g in our study; arsenic: 8.1 µg/g as against 5.19 µg/g in our study). The reason for this variation could be the method of determination of the levels of the metal. Saper et al
] used the X-ray diffraction analysis, which, by its non-destructive nature, may give higher values than those that actually exist.
Body weight change is an important index for the assessment of toxicity. In the present study, the test drug, even at the highest dose level studied, showed almost normal body weight gain. This clearly indicates that it does not cause serious organ damage or derange any physiological function.
Of the 13 biochemical parameters studied, significant changes were observed in the ALP activity at all dose levels. This enzyme is synthesized in the liver and bone. It is produced by the osteoblast of the bone and is associated with the calcification process. It is localized in the cell membranes and is associated with the transport mechanism in the liver, kidney and intestinal mucosa. Moderate (two to three-times) increase in the ALP level is seen in hepatic diseases such as infective hepatitis, alcoholic hepatitis or hepatocellular carcinoma.[19
] Because corroborative changes in histopathological study could not be seen in the liver, kidney and heart, the involvement of these organs may be ruled out. It is possible that the observed effect may be due to the increased osteoblast activity. Moderate elevation was observed in the serum total bilirubin level, although this was also not dose dependent and could have resulted from a higher destruction of the RBCs. However, hematological investigations show only a marginal change in the RBC count and marginal to moderate decrease in the hemoglobin content. Taking these factors into consideration, it may be inferred that the elevations do not indicate any serious pathology. A decrease in the serum globulin was observed at higher dose levels. This parameter is influenced by many factors due to its varied components. Because no degenerative changes could be observed in the thymus, spleen and lymph node, immunological toxicity can be ruled out.
A decrease was noted in the total WBC count. This decrease may be indicative of suppression of the formation of WBCs. However, as the effect was not dose dependent and not seen at a therapeutically equivalent dose, it may not be of any serious therapeutic concern. Changes observed in the RBC and platelet-related parameters were not remarkable.
No significant change in the cytoarchitecture of the important organs studied could be observed. This clearly indicates that the formulation has no serious toxicological implications.
A higher level of lead is reported to produce neurologic, immunological, reproductive and renal toxicity.[20
] In the present study, no behavioral or neurological toxicity was observed in the behavioral studies. Because the spleen, thymus and lymph node were not affected structurally, serious adverse effects on the immune system do not seem to be involved. However, functional effects cannot be ruled out as no cytokine assay was carried out and a fall in the WBC count was observed. Similarly, the kidney and reproductive organs from the test drug-administered groups did not exhibit any degenerative change on histological examination. Further, the biochemical markers related to the kidney and liver were not affected.
In spite of the presence of lead in levels more than the permitted limits, serious lead toxicity did not occur. The only observation that was seen included fall in WBC counts and elevation of ALP, for which there was no other corroborating clinical, biochemical or histopathological explanation. There could be several explanations for this. As this formulation is herbomineral in nature, there is a possibility of an interaction between the metal and plant component during preparation, which might lead to a decreased bioavailability of the metal. Secondly, the lead may not be present purely in an inorganic form. Formation of organometallic complexes may also, hypothetically, influence the bioavailability of lead. Further, the formulation contains other metal-based products, which may lead to a metal–metal interaction, modulating the bioavailability of the other.
Thus, the administration of the herbomineral formulation presents a highly complex biological situation that cannot be explained simply on the basis of simple measurements of the heavy metal content in them. Even the toxicokinetic study with tissue estimation of the metal contents may not clarify the issue unless the speciation of the metal in the biological system can be established. Thus, the only reliable indicator of safety of these preparations is assessing their effect in biological systems. In the present study, this was carried out in the form of a chronic toxicity study (120 days). In spite such a long duration of administration, no serious toxic effects could be observed, especially at doses equivalent to the clinically advocated dose.
In conclusion, this study indicated that Mahayograj guggulu is generally well tolerated. The only possible cause for concern was the moderate elevation of ALP activity and moderate decrease in the total WBC and lymphocyte count and the tendency toward a decreased platelet count, all of which suggest myelosuppression. Importantly, none of the effects observed were dose dependent in nature, and a histopathological examination showed an almost normal cytoarchitecture of the organs studied, ruling out a serious toxicity potential at the therapeutic dose levels.