Basic review of herbal toxicology, issues of herb/herb, herb/drug interactions.

1. Safety of Herbal Medicine
Dr. Michael Tims

2. Covered
• Types of adverse reactions
• Acute or chronic
• Organ system/s affected
• Special forms

3. Types of adverse reactions
• Type A reactions
• Acute reactions, pharmacologically predictable, dose dependent
eg. belladonna alkaloids (atropine) – anticholinergic symptoms
• Type B reactions
• Idiosyncratic or immune reactions eg. hepatotoxic reactions to
chaparral, kava
• Type C reactions
• Delayed reactions during chronic therapy, pharmacologically
predictable eg. hypokalaemia (muscle weakness) from
anthraquinone glycosides (senna etc.)
• Type D reactions
• Certain delayed effects such as tetragenecity, carcinogenicity eg.
Aristochlia – nephrotoxin
De Smet, P.A.G.M. 1996. Towards safer Herbal Medicines. 4th ESCOP
symposium, Cologne. In European Phytojournal 1

4. Acute toxicity
• Ability to do systemic damage after a one-time
exposure of short duration ( up to 2 weeks)
• Clinical indications for acute toxicity include:
• Changes in breathing rates
• Pulse and heart rate
• Motor and reflex activities
• Vomiting
• Swelling or redness of skin

5. Examples of LD50 values
Substance LD50 value mg/kg
Dioxin 0.001
Ricin C 0.25
d-Tubocurarine 0.5
Nicotine 1
Strychinine 2
Caffeine 127
Atropine 622
Aspirin 1000 (1/4 pound per 200 pounds)
Eucalyptus oil 2480
Salt 3000
Lavender oil 4250
Hawthorn 6000
Ginkgo extract 7700

6. Root, leaf, seeds
Poke Root
• Phytolacca decandra or P. americana, Phytolaccaceae
• Acute toxicity
• Saponin ld50mouse 181 mg/kg
• Pokeweed antiviral protein ld50mouse 1.2 mg/kg
• Pokeweed mitogens Pa1-Pa5 ld50mouse 0.065 mg/kg
• Case reports toxicity now and in 19th centur

7. Chronic Toxicity
Pyrrolizidine Alkaloids
Comfrey, Symphytum officinale
• Toxicity activated by gut flora altering parent
molecule
N-oxide → free base
• Related to the R-groups of pyrrol ring
• Active state very reactive - intercalates with DNA

8. Pyrrol Ring and R-groups

9. Effects on Humans
• Acute veno-oclusive disease (VOD) - reversible
once ingestion stops
• Chronic cirrhosis (hardening of liver) - remains
once ingestion stops
• Chronic carcinoma (product of DNA binding) -
remains once ingestion stops

10. Exposure Routes in Humans
• Drought and famine conditions
• Medicinal plant use
• Milk and Honey - Europe and England

11. Toxicity Risk Assessment
• Non-representative animal models used - rats display a
different reaction to PA poisoning than humans.
• Route of administration wrong. Some studies with
animals injected the PAs and thus result in increased
toxicity of the PAs.
• Mutagenicity - as interpolated in mice studies, requires
very large dose
• Topical absorption limited, no N-oxide conversion, easily
excreted

12. Idiosyncratic Toxicity
• Chaparral or creosote bush (Larrea divaricata, subspecies
tridentata),
• Evergreen desert shrub found in the southwestern United
States and Mexico.
• Leaves are ground into a powdered extract brewed into
tea
• Multiple active constituents
• Nordihydroguaiaretic acid (NDGA) potent antioxidant
properties

13. • Hepatotoxicity from chaparral is rare, displaying
idiosyncratic features
• In some cases leading to acute conditions of the liver,
including failure
• Recurrence after re-exposure has occurred
inconsistently

14. Hepatotoxicity
• Susceptibility: high blood flow to the liver (30% of cardiac
output), and “first pass effect” caused by the delivery of
blood from the intestines to the liver via the portal vein
• May involve fatty degeneration of the liver (by ethanol)

15. Nephrotoxins
Cell death leads to acute tubular necrosis characterised by
impaired reabsorption of water and electrolytes

16. Nephrotoxicity of Herbs
• Majority of reports - aristilochic acid and Chinese herbs
• One case of Glycyrrhiza induced renal failure in patient
who ‘consumed large amounts’ over 7 years (fatal)
• One case of wormwood essential oil induced renal
failure following consumption of 10ml (recovered)
• Two cases of nephropathy following consumption of
complex herbal mixtures - 1 western, 1 TCM.
Wojcikowski et al. (2004) Medicinal herbal extracts – renal friend or foe? Part 1.
Nephrology 9: 313-318.

17. CNS Toxicity
• Factors that increase susceptibility to xenobiotic
toxicity
• Receives14% of arterial blood
• Functions at a high metabolic rate
• Contains high lipid levels

18. Neurotoxins
• Neurotoxins include alkaloids such as quinine and
cocaine
• Adulterants such as mercury and lead, as well as
organophosphate and organochloride pesticides.
• Many essential oils are neurotoxic - cross the brain barrier
H3C
CH3
H3C
O
(-)-Camphor
- a dicyclic ketone

19. Contact Organs
Mucous membranes - susceptible to injury through
direct contact with poisons or irritants.
•Skin - latex-containing species of Euphorbiaceae family
and nettles (Urtica spp.)
•GIT – saponins, alkaloids, tannins, volatile lactones,
essential oils and oxalates
•Lungs - high dose of cyanogens or cyanogenic glycosides

20. Special forms
• Mutagenicity – genetic mutations
• may lead to carcinogecity
• changes to reproductive capacity
• Carcinogenicity – cancer causing
• safrole, estragole, methyleugenol and β-asarone
found in essential oils of sassafras, basil, tarragon,
calamus and Melaleuca bracteata
• Teratogenesis - formation of birth defects

21. Herbs and Reproductive Toxicity
• Little research
• Inconsistent information
• Many of the abortifacients contain toxic ketones -
sabinyl acetate from Juniperus sabina, camphor from
rosemary and pulegone in pennyroyal and buchu

22. Some Points to Consider
 How many toxic compounds?
 Where are the toxic compounds located?
 When does concentration peak?
 How do humans interact with the plant?
 If ingested, does human gut flora ↑ or ↓ toxicity?
 How difficult is it to ingest a toxic dose?
 Where do toxic effects occur in humans?