Pyrrolizidine-alcaloïden

Pyrrolizidine alkaloids are heterocyclic organic compounds. They occur in nature in more than 6,000

plants (in excess of 300 plant species of up to 13 families, mainly in the families of Boraginaceae (all

genera), Asteraceae (tribes Senecioneae and Eupatorieae) and Fabaceae (genus Crotalaria)) [PRAKASH

et al. 1999]. More than 350 different PAs, excluding the N-Oxides, were described up to now and it is

assumed that about half of them are hepatotoxic [FU et al. 2004].

Furthermore, both the composition and concentration of PAs may fluctuate according to climatic and

environmental conditions, the age and part of the plant as well as the variety (genotype/chemotype)

[HOOGENBOOM et al. 2011]. Thus, all known PAs of a PA-containing plant are not necessarily present at

the same time. Furthermore, the same species growing in different locations or in different seasons

may contain different alkaloids [MATTOCKS 1986].

Hepatotoxicity following the intake of toxic, unsaturated PAs is established. However, the dose-effect

relationship remains unclear and inter-individual differences in susceptibility are large. The

intoxications with toxic, unsaturated PAs were described as an “iceberg disease”. That means that only

a very few apparent cases (except for sporadic epidemic situations) with many subclinical

manifestations are known. However, most of the cases will remain unrecognised. Since the alkaloids

are eliminated within 24 h, suspicion could not be confirmed, as the symptoms may take several days

or months to appear. Furthermore, hepatotoxicity caused by PA may easily be misinterpreted as the

result of other aetiologic factors, such as alcohol abuse for example [STICKEL & SEITZ 2000, EDGAR et al.

2011].

However, there are no substantial, long-term follow-up data to assess whether exposure to toxic,

unsaturated PAs results in increased incidence of chronic liver disease or cancer in man. Available

clinical and experimental data suggest that a single episode of PA toxicity and possibly also a longterm

low level exposure may lead to cirrhosis of the liver. Toxic, unsaturated PAs could also be

possible carcinogens in man, since a number of them have been demonstrated to induce cancer in

experimental animals. In addition, in several instances of human toxicity, the reported daily rates of

intake of PAs were in close range of those known to induce tumours in rats. Estimates of intakes

causing toxic effects in human beings indicate that they are more sensitive than rats and domestic

animals. Rats dosed with lasiocarpine at a rate equivalent to 0.2 mg/kg bw/day developed tumours.

Pigs fed monocratoline equivalent to about 0.08 mg/kg bw/day developed chronic liver damage in

several months. The lowest intake rate causing VOD in a human being was estimated to be

0.015 mg/kg bw/day, and was a result of a self medication with a comfrey preparation.

The International Agency for Research on Cancer (IARC) evaluated several PAs for carcinogenicity in

1976 and 1983. It was concluded that there was in experimental animals "sufficient or limited

evidence" for the carcinogenicity of monocrotaline, retrorsine, isatidine, lasiocarpine, petasitenine,

senkirkine, and of extracts of the PA-containing plants Petasites japonicum, Tussilago farfara,

Symphytum officinale, Senecio longilobus, Senecio numorensis, Farfugium japonicum and Senecio

cannabifolius. The main target organ is the liver, where liver cell tumours and haemangioendothelial

sarcomas were observed. In some instances, tumours in extra-hepatic tissues (lung, pancreas,

intestine) were also observed, namely with monocrotaline, retrorsine, and lasiocarpine. Some PAs, for

example, retrorsine, have been shown to be carcinogenic after a single dose. The pyrrolic metabolites

have also been shown to be carcinogenic for rats. However, IARC concluded that the compounds are

not classifiable as carcinogenic for humans. Due to the NTP data on riddelliine carcinogenicity, IARC

changed the classification into “possibly carcinogenic to humans”, while NTP itself concluded that

riddelliine is “reasonably anticipated to be a human carcinogen” [IARC 2002, NTP 2008].

In some countries and in some areas of usage, limits for the toxic, unsaturated PA intake were set (see

also table 1). The basis for the calculations is often not known.

Table 1: Proposed tolerable levels of exposure for unsaturated PAs and their N-Oxides Authority TDI for unsaturated PAs and their N-Oxides Bundesanzeiger (1992) 1 µg/day (max. 6 weeks per year) 0.1 µg/day (no restriction) (for medicinal products only) BfR (2011) 0.007 µg/kg/day Food Standards Australia New Zealand (FSANZ) (2001) 1 µg/kg bw/day (provisional) (TDI based on avoidance of VOD, cancer risk considered not proven) Rijksinstituut voor Volksgezondheid en Milieu (RIVM) (2007) [KEMPF et al. 2010b] 0.1 µg/kg bw/day (based on virtual safe dose of 0.43 ng/kg bw/day) Committee on Toxicity (COT) (2008) 0.1 µg/kg bw/day (non-cancer unlikely) 0.007 µg/kg bw/day (cancer unlikely)

Low level, intermittent dietary exposure to toxic, unsaturated PAs can be expected, so that slowly

progressing chronic diseases such as cancer, cirrhosis and pulmonary hypertension are possible

outcomes from eating foods sometimes containing relatively low levels of PAs. Hepatotoxicity may not

always be the most prominent effect. P450 enzymes are also subject to induction by many (herbal)

medicinal products and their use could significantly enhance the toxicity of PAs in the diet. The

extended time period of progressive chronic disease development adds to the difficulty in identifying

Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)

dietary sources of PAs. It has to be considered that honey-containing products as mead, candy etc.

may also contain toxic, unsaturated PAs, as shown by KEMPF et al. [2011]. Familial susceptibility to PAs

toxicity can also be expected. It should not be forgotten that anti-mutagenic compounds will also be

ingested from food plants so that the impact of both mutagenic and anti-mutagenic compounds will be

modulated by polymorphisms in genes associated with nutrient or xenobiotoc uptake, distribution and

metabolism [FERGUSON & PHILPOTT 2008].

Because of their known involvement in human poisoning and their possible carcinogenicity, exposure

to toxic, unsaturated PAs should be kept as low as practically achievable, as also pointed out by IPCS

1988, EFSA 2007, and BFR 2007. According to the published literature, it is possible that the average

dietary daily intake might already be more than the amounts of toxic, unsaturated PA which are seen

to be safe. According to KEMPF et al. 2010b and EDGAR et al. 2011 the daily amount of PA-intake via

honey can easily reach 10-100 µg PA/day. Other sources of toxic, unsaturated PA containing food (e.g.

milk, convenience products, which may contain PA-traces, and meat) are known so that the actual

exposure cannot be assessed.

Recommendations

Because of their known involvement in human poisoning and their putative carcinogenicity, exposure

to toxic, unsaturated PAs should be kept as low as practically achievable.

In the evaluation of HMPs/THMPs containing toxic, unsaturated PAs Member States should take steps

to ensure that the public are protected from exposure and the following thresholds should be applied.

Even though that the HMPC allows the TTC concept for the risk evaluation of herbal preparations

containing identifiable genotoxic compounds this applies only to preparations/compounds where an

established safety assessment method cannot be applied by the lack of data [HMPC 2007; BUCHOLZER et

al. 2014]. The existing data on toxic, unsaturated PAs were seen by different bodies sufficient to allow

a specific safety assessment [EFSA 2011].

Oral use

Risk assessment by various scientific organisation [COT 2008; EFSA 2001] deduced a permitted daily

intake of 0.007 µg PA/kg body weight. Assuming a 50 kg person this would mean a daily intake of

0.35 µg per day (from all sources: food and herbal medicinal products) for adults.

The potential daily intake of toxic, unsaturated PAs via food cannot be ignored especially as

consumers/patients are not able to avoid them. On the basis of the available kinetic data, it seems

clear that ingested PAs will be absorbed and metabolised.

The HMPC concluded that the short-time (maximum 14 days) daily intake of 0.35 µg toxic, unsaturated

PAs/day from herbal medicinal products might be acceptable.

Sensitive groups

Children:

If children are included in the usage of certain products the daily amount of toxic, unsaturated PA has

to be adjusted to the body weight of the age group: e.g. body weight of 20 kg would lead to an

acceptable short-time (maximum 14 days) daily intake (herbal medicinal products) of 0.14 µg toxic,

unsaturated PA/day.

For ~18% (average) of the European population the body weight is given with less than 60 kg [EUROPEAN COMMISSION

2006]. These number would increase to up to 30%, if only taking into account woman. Therefor the calculation is linked to

a body weight of 50 kg.

Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)

EMA/HMPC/893108/2011 Page 19/24

Pregnant and breast feeding woman:

Sensitive groups such as pregnant and breast feeding woman are also covered by the limit calculated

above. If these limits are complied with, the chapter 4.6 of the SmPC of the products concerned should

be phrased according to the “Guideline on risk assessment of medicinal products on human

reproduction and lactation: from data to labelling” (EMEA/CHMP/203927/2005).

Cutaneous use

Until now only rudimentary data concerning absorption of PAs through the skin exist. The study by

Brauchli et al. (1982) suggests that at least in rats, the dermal absorption could be 20-50 times less

than absorption via the intestinal route. The used test model (rat) is not sufficient for the risk

assessment in humans.

It is to ensure that the amount of toxic, unsaturated PA within the daily dose is <0.35 µg for adults

(short-time usage). The use is restricted to intact skin.

Higher contents of toxic, unsaturated PA within the products would be possible if for the relevant

product (means the relevant matrix, because absorption might be greatly influenced by the excipients,

for instance essential oils as enhancers) low absorption rates (generated with modern analytical

techniques; in animal species which are more comparable to human beings in relation to the skin or in

vitro human skin preparations) can be shown, not exceeding the daily intake of 0.35 µg toxic,

unsaturated PA for adults.