Hi Pallavi

Anything taken in excess is not good and that's why we are advised to do the toxicity studies on animals before human trials. So we find the optimum dose for any drug or the bioactive fraction in question. As far as pure compunds are concerned, it would not be correct to say them 'toxic'. The correct word should be 'potent'. They may be toxic or non toxic. But when potent, they show their effects in small doses too which are not evident when in a fraction or combination.

Phytochemicals have their inherent properties and pharmacological actions on the human body which may be beneficial or harmful.  

Regards 

Every plant is having many phyto chemicals, each one is having different action or actions. The herbal extract is having many phytochemicals, the action may be synergistic or antagonistic, all may not have same action, if antagonistic chemicals are more then reverse may be seen and vice versa. 

If dose is exceeded then also toxicity is be observed.

Purified plant constituents are not fundamentally toxic. They must be considered potentially toxic as they might show activities distinct from the herbal extract, especially when looking at minor compounds that would not be ingested in sufficient amount from a  total herbal extract.

The opposite case is also possible, i.e. an extract may show activities that cannot be linked to single constituents.

Dear Dr.Pallavi Dhakur, I guess that your question is based on the premise that you are talking of the same dose of a phytochemical (constituent), if you deal with either a pure fraction or a crude phytocomplex. In this case, the final outcome depends on whether the single constituents in the phytocomplex act antagonistically or not. In the former case toxicity may increase by proceeding through the purification process of the active principle. If toxicity of the active principle is great (e.g., alpha- and beta-amanitin of the Amanita phalloides), however, it is very hard to prove that the toxicity of the phytocomplex is smaller as compared to that of the pure constituent. 

Dear Pallavi Thakur,

What is the nature of toxicity that you are implying? Toxicity generally refers to the extent to which a substance (chemical, toxin, poison, etc.) induces harmful effects in humans or animals.  Then there is acute toxicity, and chronic toxicity. Chronic toxicity is the capacity of a chemical (or physical agent) or a chemical mixture to bring about harmful effects over an extended period of time, largely upon successive or continuous exposure; this toxicity on occasion can extend to the life time of the organism exposed. Chemicals (and particulate irritants) foreign to body can cause respiratory and other disorders (acute and chronic inflammatory responses). When the immune system is affected it is manifested as allergy and asthma and so on (hypersensitivity). Agents possessing toxic potential can affect erythrocytes and immune cells. Toxicity to cells is cytotoxicity. Some chemicals are toxic to organs and cultured cells. Several plant derived chemical constituents affect chromosomes and bring about genotoxic effects. Plant originated molecules may also be toxic to bacteria and other microorganisms.  As we know, it is not that naturally occurring substances are completely devoid of toxicity. Table sugar can be toxic to humans at massive concentrations. Toxicology tells that any substance can be toxic depending on its dose and duration of exposure of the target.

If I understand you correctly, what you are saying is that bioactivity guided fractionation is warranted in order to deduce the potential individual mechanism(s) of action, and to assess efficacy of phytoconstituents or, very simply, plant compounds. And, purification/fractionation of the source material is criticized in view of the associated toxicity of pure compounds. Is the criticism levelled on the following basis? Pure chemicals originating from the fractions display toxicity at any rate and, therefore, fractionation and purification are pointless. Is that how it is criticized?

“What is the reason behind the toxicity of these pure fractions?” Since you have used the words, “linked toxicity” of pure compounds, by “pure fractions” do you mean pure compounds? It is good to know. Then one could try to answer your next question, “What is the fundamental reason associated with toxicity of purified phyto-constituents?” I presume that by “purified phytoconstituents” you mean pure molecules.

The word, phytoconstituent, has been variably used in publications. For instance, this word has been employed to denote quercetin, silymarin, ellagic acid, curcumin, resveratrol, tea flavans/polyphenols, cocoa catechins, ascorbic acid, etc., and includes single, distinct compounds and mixtures. Toxicity of a single phytochemical in many cases is intrinsic to the molecule. Toxicity is expressed as a function of concentration of the test substance. It depends on the kind of toxicity one is intending to study and the type of target system. In evaluations of phytochemicals we are largely dealing with in vitro toxicity. Toxicity of a phytochemical is not random or ambiguous. The manner in which it is evaluated may be. It must be mentioned that the concentrations of the plant compounds used in evaluating toxicity and pharmacologic activities are often supra physiological. Many plant derived single molecules are endowed with high reactivity, which is integral to their nature, and propensity to interact with macromolecules (example, proteins). Limited intestinal absorption and rapid elimination provide a built in safeguard against their highly intense pharmacologic actions. 

A phytochemical, depending on its concentration, might have dual effects, toxic action as well as potentially beneficial activity (it might potentiate or antagonize). 

 As we do fractionation/purification the concentration of the active constituent (target moeity) increases. In terms of activity the purified compound becomes potent (shows more activity at low concentrations). There is relationship between purity and biological activity of natural products. The associated compounds or the so called impurities may show synergistic effects or antagonistic effects showig higher or lower biological activity than its pure form. Thus the activity varies with the purity as well as the chemical composition. The toxicity is dose dependent. Anything in excess is a poison. The pure compounds are not toxic if given in appropriate doses. Please find here the link for publication where purity-activity relationship for ursolic acid is studied. Link:http://pubs.acs.org/doi/abs/10.1021/np800329j

Toxicity depends on different factor. A plant has many phyto-active compound.If u dissolve your plant in potent methanol as a solvent, it is also partially toxic. plant also may be toxic for its phyto-active compound. its may show cellular toxicity when administered a large dose or lethal dose. so for clinical trial we suggest to do Acute toxicity test in animal model  to measure the toxicity level of plant extract.

Dear Dr. Sendker,

Your statement is significant. Several factors may account for the presumed actions of extracts such as potential synergism between different compounds, the potential to act on several targets, etc. Soy extract has been shown to be pharmacologically more potent than genistein, an important isoflavone molecule present in soy extracts. Similar observations have also been made in studies on estrogen binding (type 2) sites. Identification of active molecules in a plant extract may be depend on the methods employed for extraction. This could be a crucial factor. The herb, Arnica, has been widely in use although there has been scant information on the safety and toxicity of the ligands (pure constituents) that might be found in it. The cytotoxicity of the major constituents of this plant (flavonoids, sesquiterpenes and phytosterols) has just been evaluated, and the activity is attributed to sesquiterpenes.

Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae). 

José Luis Rodríguez-Chávez, Elvia Coballase-Urrutia, Gloria Sicilia-Argumedo, Teresa Ramírez-Apan, Guillermo Delgado.  Journal of Ethnopharmacology, Volume 175, 4 December 2015, Pages 256-265.

Related article: A.Z. Ameni, O.A. Latorre, L.M.B. Torres, S.L. Górniak. Toxicity study about a medicinal plant Casearia sylvestris: A contribution to the Brazilian Unified Health System (SUS).  Journal of Ethnopharmacology, Volume 175, 4 December 2015, Pages 9–13.

Miss Pallavi

Each and every natutal products are toxic when it will be taken at very high dose.

So first optimize its IC 50 then check its toxicity..then you can calculate its safety 

Profile..how much is this compound are safe or potent. Its toxicity well defined 

When it is checked in animal model.

Activity and toxicity profile of mother fraction is not a proof to resemble the similar 

Activity and toxicity pattern as in case of pure herbal products too.

HI,

As all experts said, Phyto or Synthetic compound, each molecule have threshold level in the body. when the concentration exceeded this threshold  limit body tent to react either positive or negative way. positive is called efficacy and negative is toxic. in this case even water can be a toxic when it taken more then the threshold limit. so, pure compounds of synthetic drug need to dilute to perfect efficacy and positive effect. if it has given pure( high dose) it has toxic effect. same way herbal compounds naturally diluted form in the plant and its directly given along with co existing phyto compounds for its efficacy. when modern science try to purify to high pure. then it need to be diluted to its own level as like synthetic drugs.

By mother nature, phyto bio beneficial molecules exist with number of other molecules which positively help the particular phyto compounds to function inside the body.  

Good Luck

Dear Pallavi Thakur,

The word “toxicity” may be defined as the relative capacity of an agent to cause adverse effects in organisms. It refers to the extent to which a chemical agent causes a poisonous effect or an adverse response in a target. Toxicity is dependent on several factors such as dose, frequency and duration of exposure, site, route of exposure, interspecies and intraspecies variations, structure and shape of the chemical and individual human factors. Toxicity is the inherent nature (and intrinsic hazard) of a chemical agent.

 "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." This early observation concerning the toxicity of chemicals was made by Paracelsus in the 15th century. The science of toxicology was connoted as "the science of poisons." In its broadest sense, toxicity concerns the potential interactions between chemicals and biological systems. Toxicity can be defined as the relative ability of a substance to cause adverse effects in living organisms. This "relative ability” is dependent upon several conditions. As Paracelsus has suggested, the quantity or the dose of the substance determines whether the effects of the chemical are toxic, nontoxic or beneficial.

In addition to dose, other factors may also influence the toxicity of the compound such as the route of entry, duration and frequency of exposure, interspecies and intraspecies variations. Although chemical reactivity and toxicity are related, factors other than reactivity can contribute to toxicity. A cascade of toxicologic effects of a phytochemical (herbal here) can ensue owing to molecular initiating events in which the herbal molecule reacts covalently (or non-covalently) with macromolecules in a cell.

Individual phytochemicals from herbs can express variable degrees of activity; a number of these molecules have substantive reactivity. They can be reducing agents, in vitro metal chelators or metal complexing agents (although free transition metals are very well sequestered in biological systems), hydrogen atom donors in oxidation- reduction reactions (redox), redox active agents, enzyme modulators, etc. Many herbal compounds possess intrinsic toxicity. The above are some of the reasons that molecules purified from herb fractionation exhibit toxicity; toxicity is a manifested property and not an "ambiguous notion".

Oxygen, a diatomic element, is considered the abundant element in the planet. The potential for oxygen to oxidize other molecules makes it toxic. Molecular oxygen possesses two unpaired electrons in separate orbitals in its outer shell, and, therefore is a radical (diradical). The two unpaired electrons of oxygen have opposite spins. Oxygen is a weak radical. It can accept one electron with an antiparallel spin to form a reactive radical (superoxide), which is potentially more toxic than molecular oxygen is. Purified compounds from herbal extracts have properties connected to oxygen related processes, metabolic processes and xenobiotic aciions.

Individual phytochemicals from herbs can express variable degrees of activity; a number of these molecules have substantive reactivity. They can be reducing agents, in vitro metal chelators or metal complexing agents (although free transition metals are very well sequestered in biological systems), hydrogen atom donors in oxidation- reduction reactions (redox), redox active agents, enzyme modulators, etc. Many herbal compounds possess intrinsic toxicity. The above are some of the reasons that molecules purified from herb fractionation exhibit toxicity; toxicity here is a manifested property and not an ambiguous notion. 

Jayaram has drawn attention to a crucial point here. The threshold level of toxicity signifies the lowest concentration or dosage of a substance that consistently produces symptoms of toxicity as noted by a change in physiological response. Human exposure threshold value for chemicals is a dose below which there is no significant risk to human health.  Experts consider that here is no threshold dose of asbestos below which there is no risk. Low exposures higher than background levels are thought to be capable of causing mesothelioma (of the pleura; cancer of the lung) in humans.  

 Thanks Dr Chithan for appreciation. please keep going for many more valuable answers.