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 Herbal Medicine: German Translation of PZ 39 (135): 6-7, 97-98, Sept. 1990  
 
Information on Pyrrolizidine Alkaloid-Containing Human Medicines AMK. The expert commisions for herbal, homeopathic and anthroposophic medicines, the members of which are selected from among prominant members of each discipline, have worked out preparation monographs for a series of remedies, which contain pyrrolizidine alkaloids (PA). PA are naturally-occuring constituents of different medicinal plants. Some of them with certain chemical characteristics are suspected to be the cause of liver-damaging and carcinogenic effects in humans and animals.

In a first hearing on PA, in 1988, the BGA asked manufacturers to declare their position on possible health risks of PA-containing remedies. The Governement Health Office (BGA) has now made its evaluation on the basis of the first hearing, where all results from the expert commissioners, and numerous positions given by manufacturers, doctors, patients and scientists were considered.

The BGA has presently undertaken a further, written hearing with expert representatives from pharmaceutical manufacturers utilizing plants with certain PA for the production of plant-based remedies. In this new hearings questionaire, the safety measures that are considered necessary for diverse groups of PA-containing herbal remedies are presented in detail. These are coming in from manufacturers and will be evaluated.

*The BGA suggests a maximal daily dosage for remedies intended for internal use, and another for remedies for external use, as well as a total application period of 6 weeks per year.

*Special caution is advised for pregnancy and nursing.

The BGA is thereby following the recommendations formulated by the expert commissioners, which in their understanding, is the precondition for the safe use of these herbal remedies. The comprehensive discussion initiated by the BGA regarding the risks of PA-containing remedies has thereby, through broad participation of expert circles, led to an extensive agreement on the measures offered for the protection of patients.

A final decision will come about after evaluation of the awaited statements (questionaires).

As was already reported last week (see Pharm. Ztg. 38/1990, p. 7), the BGA has, in the frame of its progressive (sequential) plan (step 2), sent a new hearings-letter regarding relevant pharmaceutical enterprises relating to PA-containing remedies. The distribution list enclosed with the letter, comprised 124 pages and listed 1600 finished products. For the most part, to be sure, we are dealing with name-brands (especially teas) from pharmacies, drug stores and health-food stores. Exempted from the prescribed measures of the BGA are remedies which from among the series of questionable plants, contain Eupatorium perfoliatum, because no PA content has been provable. Likewise exempted are remedies produced by a spagyric process, which includes a water steam distillation as well as ash.

The commission E of the BGA meanwhile has concluded and published preparations-monographs for the following PA-containing herbal remedies (BAnz [official notice]- Nr. 138, dated 7/27/1990, see Pharm. Ztg. 31/ 1990, p. 65)

-- Coltsfoot flowers/herb/root

-- Coltsfoot leaf

-- Petasites hybridus (butterbur)/Petasites leaf

-- Petasites rhizome

-- Senecio herb

-- Comfrey herb/leaf

-- Comfrey root

A permit (with certain restrictions) can be supported only for coltsfoot leaves pestwurtz root (Petasites) and for comfrey preparations for external use. Among the restrictions is the limitation of the duration of application to no longer than 4-6 weeks per year, and a maximum value of PA with a 1,2 unsaturated necine-structure.

**The BGA looks, among other factors, at the results of the preparations commission (commission E), and announces the following measures, which are to be finalized within the next 6 months. As the past teaches us, we have to count on intense private and public discussions, thorough reasoning, including a review of the available literature, which is to be printed along with the results.

I.

1. In the case of remedies for external application, with monographs of a recongnized or specific area of use and effectiveness (paragraph 25, 7 AMG), the daily exposure may not exceed a maximum 100 micrograms PA with a 1,2 unsaturated necine structure, inclusive of their N-oxides, according to the instructions enclosed in the product package.

The recommended duration of application for corresponding remedies for external applicaiton is to be limited to 6 weeks maximum per year. In quoting contraindications, it is to be noted, that the application may happen only with intact skin. The application during pregnancy should result only after consultation with a doctor.

2. In the case of remedies for internal application with monographs of recommended areas of use and effectiveness, according to paragraph 25 7 AMG, the daily exposure may not exceed a maximal dosage of 1 microgram. For the application of coltsfoot leaves as a drug for a tea infusion, exposure may not exceed 10 micrograms PA with a 1,2-unsaturated necine structure, inclusive of thier N-oxides.

The recomended duration for the application of corresponding remedies is limited to six weeks per year maximum. Pregnancy and nursing periods are to be stated as contraindications.

3. Remedies in which the daily exposure does not exceed a maximal doage of 0.1 microgram PA (for internal use) and/or 10 micrograms PA for external application, with a 1,2 unsaturated necine structure inclusive of their N-oxides, according to instructions enclosed in the package.

The proof of the observance of these concentrations for each [rank] is to be stated on the basis of a valid analysis (see our communication of August 10, 1988) on a suitable sample (for instance raw plant material or mother tincture according to HAB 1) with subsequent calculation of the amount in the finished product.

II.

The BGA intends to decree a tacit permission for remedies according to 1.1, 1.2, 1.3 for which the observation of the above-named limits has not been certified within 6 months after release of this communication.

III. For all other remedies and application areas, the intent is to recall permission.

[Reasoning]

The determining reason for the anticipated measures of the BGA is -- we refer in this to our communication of August 10, 1988 -- the following contents of critical PA are never to be looked at as being unobjectionable health-wise; this is understood from the evaluation of proven toxicologic characteristics and reports on these substances.

PA with a 1,2 unsaturated necine-structure have distinctly acted mutagenicaly, and/or genotoxically in several test systems after metabolic activation. The intensity of the mutagenic effect, measured at the lowest effect-concentration/dose did not essentially differ in experiments in which these PA were examined comparatively. At most, differences in the range of about a 10th potency were observable (1-5).

In the cancer studies on hand, distinct carcinogenic effects have been observed in diverse PA previously, especially in the liver (cancer of the liver and haemangiosarcoma) with daily doses between 0.36 and 10 mg/kg KG (6). In this, however, it has to be considered that the real lowest carcinrogenic dosages must be essentially lower, in practical application, because the ones tested have already shown a distinctly carcinogenic effect.

The number of occuring tumors and the time span of their inductions, (and/or) latency, until their appearance depend on the strength of the dosage (7-17).

Each of the carcinogenic, and/or mutagenic potencies of the above-described PA lie in approximately identical areas of magnitude. Therefore, a differentiating consideration of the type of different PA in the various relevant plants, does not appear necessary.

The existing data give grounds for suspicion that the carcinogenic effects of these PA observed in animal experiments rests on their proven mutagenic characteristics. The suspicion is additionally supported in that the mechanism of damage through these PA is to be seen in the alkylizing characteristics of metabolites (pyrrole derivatives) (18-21). In this, whether the PA leads to acute damage, especially in the target organs, liver, lungs, and blood vessels, depends on the dosage (22) or duration, because the long continued effect of small dosages, leads to tumorous growths (7-17).

There are clear reports of acute and chronic damage in humans and animals (23-27) and carcinogenic effects are provable in animals (28, 29). Because it has to be assumed that the mechanism for acute, chronic and cancerogenic effects is the same, it is likewise to be assumed that the carcinogenic effets would also apply to humans.

The BGA embraces the fundamental assumption that every substance which has proven itself carcinogenic in animal tests is also able to cause cancer in humans, because in reverse every proven carcinogen affecting human beings, has also caused positive results in animal tests. An exception to this rule for evaluation, is certainly permissible, when a certain effect occurs specifically for a species, as has been, for example, observed for the metabolism of PA involving guinea pigs (30). Such differences do however not exist, between the metabolisms of PA in rats and humans.

The BGA has oriented itself in the evaluation of these carcinogenic substances, by the present scientific understanding, as it is for example, documented in specialist directives of the European Union, and it correstponds to the recommndation of the Senate Commissions of the German Research Association (Society?).

The references on the testing of the carcinogenic effects, corresponding to the (enclosure) supplement (III 83/571) (appendix?) have been formulated for the purpose of admitting new remedies, but the expert evaluations underlying these requirements are valid in other circumstances and ought to applied correspondingly. Thereby, the extrapolation of appraisal of the data received in animal tests, onto humans and the herein applied doses is especially addressed [in the paper of the previous sentence].

It is noted, that it is difficult to declare a compound as not being carcinogenic to humans when it has proven carcinogenic in animal tests.

On the probablility of occurance, it is stated that the danger of cancer is higher in humans, when there is a large number of malignant tumors in a particular kind of tissue (e.g., hemangiosarcoma in rats' liver after certain PA and cancer of the liver itself), when the test substance is administered in a way that is anticipated in humans (this is also the case with certain PA) and when the dosage is equal or lower than the dossage which induces the mildest toxicity (which is also the case with certain PA).

As, on the other hand, there are no exonerating findings (reports) (e.g. a clear latency phenomenon) and arguments based upon them which could contribute to a more favorable evaluation of PA-induced existing tumors, there exists justified cause for concern, especially when including a consideration of the results of mutagenic tests, as demonstrated above.

This is also not mitigated by recognition of peculiarities in the evaluation of certain remedies, because there must be clarity on the point that fundamental differences in the evaluations of such risks have not been established sufficiently by the experts.

The BGA reasons in all these matters, that potential risks, connected with substances, are characteristics, which are relevant not only to sythentics, that is, a certain class or group of remedies; because there is no inherent or preordained, safety of natural substances as compared to synthetic substances.

Where ever there is no sufficient therapeutic relavance for a substance, the carcinogenic property whereof, having been proven by experiment, as rooted in genotoxic acitve mechanisms, has as its consequence, the recall of its permit, and/or the lowering of the unavoidable concentrations which remain below the proved limits of stated sensitive control methods.

On the other hand, through the comprehensive incorporation and receipt of results of medical evaluations of the relevant preparations Commission for particular remedies, it is guaranteed that all supportive arguments for the therapeutic application are allowed sufficient consideration.

Therefore, since the purely toxicollogically-founded admissible levels for these PA fundamentally cannot be designated, the dosages and the provisional maximal time ranges for PA-containing remedies, which arose from the official perspective (insight) as the permissible substance levels, are additionally relying (for accuracy) on the expert opinion as to their therapeutic usefullness, which each relevant commission has certified by its own expert opinion regarding the risk.

According to one expert opinion (2), the intake of 1 microgram PA/day is considered justifiable (defendable) for human beings. This dosage, e.g. related to a daily intake of tea, prepared from 5 grams of dried plant, lies in the area of 0.2 mg/kg PA in these plant parts (34). Other expert opinions (32) support this limit.

Because the liklihood of a tumor occuring depends not only on the level of substance intake, but also on the length of exposure, the term of application is limited to 6 weeks maximum. In this determination (ruling) the usual length of treatment according to indications quoted in the (relevant) monographs have been considered.

For the application of coltsfoot leaf as a drug for tea infusions a higher limiting value of a maximum of 10 micrograms per day is acceptable. With the generally short extraction time in the frame of the making of a tea infusion, only a small portion of the existant PA contained in the drug is released and taken in through the preparation.

The determination of a limiting value for topical application is raised by a factor of 100 because, as examinations have shown, in dermal applications, only a small proportion of the applied PA amount is absorbed (resorbed) (35, 36).

The daily substance level of 1 microgram and/or 10 micrograms PA/day for internal, respectively (and/or) 100 micrograms for external use over a maximum of 6 weeks as tolerated by the BGA in agreement with all participants for remedies does not correspond to a limit value according to simple experimental principals in order to quantify a damaging effect and to establish a threshold value.

Rather the risks must be seen in relationship to the expected therapeutic benefits and, in as much as they stand in a medically valid relationship, to tolerate them, under certain circumstances even if they are ireversible. Compare for this also the principal of "relationship quality" in Environmental Protection presented by Henschler (38); according to this, it is required that reversible effects, which form the basis of conventional limit values must be set into a sound relationship to ireversible effects of the new quality -- as for example mutagenicity, i.e. a certain acceptance of irreversible effects has to be tolerated.

(Our interpretation of irreversible = if a new condition is created by a remedy, and this condition is irreversible, is this new condition tolerable in relationship to the healing aspect of the remedy?--eds.)

The described procedure therefore limits the exposure to constituent levels, which are to be seen as medically sound, when the remedies are applied as determined with consideration of benefits and risks.

We are dealing here by no means with amounts which are to be seen as totaly free from risk, because the theoretical investigation of genotoxic carcinogens to date tell us that no dose can be deduced below which a carcinogenic effect need no longer be assumed.

[Investigative] Results of Preparations
In as much as monographs exist, which recognize a therapeutic effect as aknowledged, the "Preparations Commissions" relevant to the homeopathic as well as phytotherapeutic therapy modalities, also arrive at the identical medically-justifiable constituent levels in their final results.

Thus, Commission D has established that in the case of finished preparations, with usefullness certified by monographs, the daily exposure to PA must not go beyond 1 microgram/day (internal use), and/or 100 micrograms/day (external use), figured on the total alkaloid content of the mother tincture. The duration of use is to be no more than 6 weeks per year maximum.

In homeopathic remedies that are to be registered without a monograph certifying their efficacy, the exposure to PA must not go beyond 0.1 microgram (internal use) and/or 10 micrograms (external use).

Commission E has suggested a threshold value of 1 microgram PA/day and/or, in the case of coltsfoot leaf as a tea infusion, 10 micrograms/day (internal use), for medicinal plants that have monographs certifying their activity.

For external use of comfrey preparations, a threshold-limit of 100 micrograms/day is suggested. The length of use is limited to 6 weeks per year.

Thus, both commissions come to the same conclusion, that the usefulness of these substances can outweight their risk only if the safety determinants and counter-indications in their monographs are followed.

Commission C welcomes, in principal, the intent of the BGA to open up a new way through the establishment of temporarily tolerable daily dosages. It (Commission C) is of the opinion that in this way a minimizing of risks can be undertaken for the single remedy in the currently possible appropriate way with a measured consideration of the therapeutic usefullness.

With values below 1 microgram/day (internal and external use) it (Commission C) sees the application of the remedy as unobjectionable; in the case of values between 1 and 10 micrograms PA (internal and external use) it requires the listing of contraindications as well as a limitation in the duration of use. Therefore, in as much as Commission C considers higher constituent levels for daily intake tolerable, because of unresolved fundamental considerations, it (Commissions C) stands in contrast to the evaluation of one of the experts, the other commissions, and the BGA.

Because this opinion is not supported by reasons that satisfy scientific criteria, as they have been laid down in the recommendations of the EG, it cannot be followed.

Summary
The studies already performed certify that PA have an acute hepatotoxic effect and a carcinogenic effect with chronic application; therefore, they confirm the opinion stated in the expert texbooks that the hepatotoxicity and carcinogenicity of these PA is considered proven. Considering this fact, the use of higher constituent levels or an exposure of longer duration are connected with damaging effects, which go beyond the responsible measure of the insights of medical science. (vgl. xx 30 Abs. 1,25 Abs. (paragraph) 2 Nr. 5 AMG).

This evaluation corresponds to current scientific knowledge, regarding a methodical proceedure for identifying carcinogenic substances, and the interpretation of existing reports. The data are scientifically-defendable and therefore, sufficient. The demand for further evidence concerning the establishment of risk, before a decision is made, can therefore not be considered.

The risks described above are seen in a similar way by the WHO (37), which urges us to do everything to facilitate the minimization of risks in the direction of practically-reachable safe quantities.

LITERATURE

(See attached original reference list).
BGA policy on PA (PZ 39 (135) 6,7-97-8, 1990. S. Coble & C. Hobbs 8
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 About The Author
Christopher Hobbs LAc, AHG Christopher Hobbs is a fourth generation herbalist and botanist with over 30 years experience with herbs. Founder of Native Herb Custom Extracts (now Rainbow Light Custom Extracts) and the Institute for Natural Products......more
 
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