SSEN TI AL 0 IL

AFET Y III
CA RCINOGENI SIS, PHOTO TOX IC ITY

ROBERT TISSERAND

The last of a three part series based on a presentation given at

Aroma ‘95. The full transcript is published in the conference
proceedings.

I
n part one I outlined the ?? Do they express their 1979) Estragole elicited liver tumours
importance of understanding carcinogenicity when in the context of in mice after 12 months of dietary
essential oil composition and how an essential oil? administration (Miller et al., 1983) and
the chemical degradation of essential 0 Are the rodent carcinogens also in infant mice when given by
oils could have safety implications, and I also carcinogenic in humans? subcutaneous injection (Drinkwater et
compared data on human and animal 0 What level of risk is al., 1976). Methyleugenol is similarly
toxicity. In part two I elaborated on acceptable/unacceptable? hepatocarcinogenic (Miller et al.,
metabolism, neurotoxicity and the very 1982; Miller et al., 1983). Asarone was
difficult question of reproductive What evidence is there that carcinogens hcpatocarcinogenic after 13 months
toxicity. This third and final part are found in essential oils? administration by intraperitoneal
examines the controversial role of There are four chemicals found in injection (Wiseman et al., 1987). There
essential oils in cancer, and gives some steam distilled oils which are known to is no question that these substances are
well-established data on phototoxicity. be rodent carcinogens - bela-asarone, weakly carcinogenic in rodents, and
safrole, estragole, and methylcugenol. that the same chemicals are found in
These typically produce liver tumours essential oils.
(the easiest type of tumour to elicit in
experimental rodents) but sometimes Do the carcinogens express their
It is important to emphasise that there is other types. Safrole produced liver carcinogenicitywhen in the context of an
not one recorded case of any essential tumours when given subcutaneously or essential oil?
oil, or essential oil component, causing by stomach tube to infant mice Both calamus and sassafras oils have
or contributing to cancer proved to be carcinogenic in
in humans. All the data we rodents. Calamus oil
have come from (containing 75.8% 6&l-
experimental research in asarone) was weakly
rodents, and we do not carcinogenic, producing
have a very good malignant duodenal tumours
understanding of how well after 59 weeks of dietary
rodent carcinogenesis administration (Taylor et al.,
extrapolates to humans for 1967). Dietary sassafras oil
essential oils. In fact (containing 90% safrole)
several questions need LO produced no tumours after 22
be addressed in order to months, but most of the
assess the risk to humans from the (Gleason et al., 1984) and when given rodents showed tumour
1 development
occurrence of possible carcinogens in orally to adult rats (Long et al., 1963). after 24 months (Abbot et al., 1961).
essential oils: Dietary safrole produced kidney and None of Ihe other implicated essential
0 What evidence is there that liver tumours in the offspring of oils (see table 2) have been tested
carcinogens are found in essential oils? pregnant mice (Vesselinovitch et al., experimentally.
it is not surprising that essential oils Are the rodent carcinogens dose-dependent, and a compound may
containing such high concentrations of carcinogenic in humans? be safely disposed of at low doses, while
carcinogens demonstrate This is another area in which there are at high doses the detoxifying metabolic
carcinogenesis. Whether essential oils very few data to go on, since there are no pathways can become saturated. This
containing much lower concentrations records of any essential oils or essential can lead to a sudden increase in the
of these compounds are carcinogenic is oil components demonstrating a carci- amount of carcinogenic mctabolite
not known. One could speculate that nogenic action in humans. The formed. One study showed that the
other components present in the compounds found in essential oils are amount of 1 ‘-hydroxyestragole formed
essential oil might inhibit the action of very weak carcinogens indeed, but they frorn estragole increased from 1% to 9%
the carcinogen. However, one could are partially metabolised by the liver as the dosage given was increased from
equally speculate that other into slightly more powerful carcinogens. O.O5mg/kg to 1000 mg/kg
components might potentiate These, in most cases, are I’-hydroxy (Zangouras et al. 1981). Other studies
(increase) the action of the carcinogen. metabolites (see table 1). This is an have produced similar results. In
Since there is no evidence of either important consideration, since it is humans, the amount of l’-
carcinogenic inhibition or potentiation known that this meta-bolism is more hydroxycstragole found in excreted
in essential oils, prediction in this arena efficient in rodents than in humans. urine is 0.3% of the amount of
is much too speculative to be of any This means that the risk to humans is ingested estragole. The saturation issue
value. In the absence of any useful data probably lower than the risk to rodents. means that extrapolating levels of risk
we can do little else but assume that the A factor related to the relevance of from animal tests with high doses to the
risk is proportionate to the amount of animal testing is the ‘saturation issue’. human situation is not a simple matter.
carcinogen present. The metabolism of many chemicals is However, WC should remember that the
most common route drops of the oil were
of administration in
I RECOMMEND/
placed in a pot in the
aromatherapy is sauna room, not on
dermal, not oral, and the woman’s skin.
we know very little The burns were to
about metabolism of one arm and leg.
these chemicals in In a second,
the skin. more serious case
severe, full-thickness
What level of risk burns were sustained
is acceptable? following a 20 minule
Taking all of the above session on a sunbed,
considerations into which followed
account, it is possible bergamot oil
to give an indication application (private
of the level of communication). In
carcinogens in this instance, a few
essential oils which is likely to be safe or acceptable. Ensuring that exposure drops of undiluted bergamot oil were
unsafe. In some instances essential oils levels remain below these would be one rubbed on both arms and both legs
contain carcinogens as major possible approach to safety in before going into a steam room. Some 15
components (lo-go%). In these cases oral aromatherapy. minutes later the woman showered, went
administration would be unwise, as would for a swim, showered again, and then
external administration. In other cazes went on to the sunbed. (Much of the
carcinogens occur only at very low levels bcrgamot oil, by that time, would have
(0.1-l%) and in these instances external crossed the epidermis.) Severe burns
aromatherapy usage is likely to be Of all the aspects of essential oil steadily developed during the following
completely safe. In the 2-10% area there toxicology, phototoxicity is one of the 48 hours on her arms and legs, at which
may bc some need for caution, and in this best understood by the scientific time she was admitted to hospital and
group will be found some commonly used community and one of the least remained there for seven days.
essential oils such as fennel and nutmeg understood by those using essential oils The skin on her arms and legs had
(see table 3). Oral administration is not in aromatherapy; the retail consumer a roasted appearance, and some blisters
recommended for essential oils with 1% of essential oils is especially at risk. were 1Ocm in diameter. After leaving
or over of carcinogens. It is important to Since rcscarch on this began in the hospital, she was not able to return to
bear in mind that a few essential oils 1950’s, we have a very good idea as to work until her skin had healed and her
contain more than one carcinogen. which ,essential oils are phototoxic and limbs were fully mobile. Two years after
which are not, and the components the incident her limbs still have dark
Conclusion responsible for phototoxicity are streaks, and she experiences occasional
The evidence that a few essential oil largely well-known and well studied. We burning sensations on the affected areas.
components are carcinogenic in also have a very good idea how much is
rodents is convincing, although they sale in humans, how much is not, and Furanocoumarins
are all described as “weak” carcinogens. over what period of time. The most common phototoxic agents
Carcinogenicity in rodents has been An excessive reaction to sunlight are the psoralens, or furanocoumarins.
seen following administration orally, can be induced by certain chemicals, These are polycyclic molecules whose
subcutaneously, and by injection into particularly if they are applied to the structure gives them the ability to
the .abdominal cavity. There is little skin. In phototoxicity, the reaction absorb ultraviolet (UV) photons, store
doubt that essential oils containing occurs only if the sensitising agent is them for a while, and then release them
carcinogens possess carcinogenic present, and results in rapid tanning. in a burst on to the skin (Caporalc et al.,
potential. However, extrapolating The following two cases will help 1967). Phototoxic components are
rodent tests to, for instance, massage in illustrate what can go wrong: present only in a few essential oils, and
humans with essential oils is not easy. in relatively small amounls, normally
As in other types of toxicity, levels of Two cases less than 2%. However, even at this
dosage or exposure are all important, A woman was treated for minor burns level, and even if the essential oil is
and there are levels below whi& the after a 20-minute session on a sunbed, diluted to, say, 2%, they are often
risk is considered by regldatory taken immediately after a sauna bath capable of producing phototoxic effects
agencies to be negligible, and therefore with lemon oil (Anon., 1992). A few if the skin is then exposed to sunlight. If
such essential oils are used undiluted, guidelines. Any higher percentage is commonly used to manufacture
and/or if the skin is exposed to a considered as carrying a risk. A number lightweight clothing only have a sun
relatively strong source of UV light of citrus oils are not phototoxic; they are protection factor of between 5 and 15
(sunbeds or strong sunlight) very severe listed in table 6. (Dayton, 1993).
phototoxic effects The use of
can result. sunscreens, in a
There is a whole potentially
family of psoralens, phototoxic
of which the best preparation, will
known is bergapten reduce the risk of
found primarily in phototoxicity.
bergamot oil. The Common sense
psoralens and tells us that the
coumarins are risk of
relatively non- phototoxicity will
volatile molecules diminish with time
and, in the cast or following
citrus oils, tend to be application to the
found in expressed skin. In reality the
(cold pressed) oils, intensity of the
but not in distilled phototoxic
oils. It is also possible response increases
to remove (or, more correctly, When there is no risk, or a reduced during the first hour following
considerably reduce) the bergapten in risk, of phototoxicity application, remains at a peak for the
bergamot oil. The resulting oil is known There is no risk of phototoxicity if the next hour, and then decreases over
as bergaptenless bergamot, or bergamot foils are used in a product which is not the following 8 hours (see table 5).
FCF (furanocoumarin-free). This applied to the skin, or which is washed This is certainly true for bergamot oil
bergamot oil is regarded as having an off the skin, such as shampoo, bath (Zaynoun et al., 1977) and the same
inferior fragrance to the oil in its natural preparations or soap. There is no risk timescale will probably hold for
state (Dubertret et al., 1990). if non-phototoxic citrus oils are used, other citrus oils. The steady increase
IL is clear rrom the essential oil such as furanocoumarin-free and then gradual decrease
monographs published by The bergamot, or distilled oils. However, presumably mirrors the time taken
Research Institute for Fragrance distilled citrus oils tend To be used in for the furanocoumarins to reach the
Materials (KIFM), and from the Ikavourings rather than fragrances, and dermis, and then to pass beyond it.
consequent International (A phototoxic reaction
Fragrance Research Ass- 1 cannot take place until the
ociation YIFRA) guidelines, substance has crossed the
that the risk of phototoxicity epidermis and reached the
depends, not on the mere dermis.
presence of phototoxic fura- As can be seen in
nocoumarins, but on the table 5, a 0.5%
type and amount present. concentration of bergamot
Some essential oils contain oil produced no
several phototoxic fura-nocolimarins are not much used in aromatherapy, phototoxic reactions, I% was safe
which probably all contribute to photo- due CO their relatively poor fragrance arter 8 hours, and 2.5% was sale after
toxicity of the oils. impact. 10 hours. Tests were carried out on
We are concerned not only with There is no risk iI the parts of the human volunteers.
which essential oils are phototoxic, but skin to which the oils have been It is recommend that skin which
also with their degree of phototoxicity. applied are covered in such a way as to has been treated with phototoxic oils
Taget oil, for instance, appears to be prevent UV rays from reaching them. It at levels higher than the maximum
around 100 times more phototoxic than should bc assumed, for the sake of use levels, should not be exposed to
expressed grapefruit oil. Table 4 shows safety, that typical summer clothing UV light for at least 12 hours. This
the percentage dilution at which each (lightweight, lightly coloured) is UV gives a safety zone of 2 hours, and
phototoxic oil is considered safe to USC permeable, whereas more substantial assumes a maximum concentration
on the skin, based on current IFRA clothing blocks out UV Most fabrics of 5% essential oil. A 15% or 20%
concentration ol bergamot oil can mutagenicity of I’-acetoxycstragole in
still produce a phototoxic reaction bacteria. Jourrlal of the National Caww
12 hours after application (Zaynoun The great majority of essential oils arc >~~st%tute
57: 1323-1331
et al., 1977). A 0.5% concenlration 01 quite safe as used in aromatherapy, 0 Duberlret, L. et al. (1990)
xanthotoxin (very roughly equivalent but the danger areas which do exist The photochemistry and
10 undiluted bergamot oil in terins of are very real and cannot be ignored. photobiology of bergamot oil as a
phototoxic potential) continued to As I have said on many occasions, it is perfume ingredient: an overview.
produce phototoxic reactions for 36 very much in the interests of the Journal OJ Photochemistry a,nd
hours, but ceased after 48 hours aromatherapy industry to, firstly, Photobiolo~~ 7: 362365
(Zaynoun et al., 1977). agree on safety guidelines Par both 0 Gleason, M. N. et al. (1984)
the trade and the profession and, Clinical toxicology of commercial
Individual differences secondly, to implement those products, 5th edn. Williams &
In a study on 63 volunteers, diflerences guidelines. Wilktins,
in eye colour, age, sex and ability to tan The attitude of some 0 Long E. L. et al. (1963) Liver
did not significantly affect phototoxic aromatherapists seems to be one of tumors produced in rats by feeding
responses to bergamot oil, but skin ignoring essential oil hazards, and safrole. Archives of Pathology 75: 595-
colour was a significant factor pretending they simply do not exist. 604
(Zaynoun ct al., 1977). There was no This is an unhealthy and unrealistic 0 Miller, J. A. et al. (1982) The
statistical difference between those with attitude. It is only through very metabolic activation and
skin described as fair, sallow and light thorough research of the subject that carcinogenicily of alkenylbenzenes
brown. The average concentration of we will be able to distinguish the real that occur naturally in many spices.
bergamot oil required to produce a hazards from Ihe illusory ones. Carcinogens and Mutagens in the
phototoxic response in these Whether we are manuracturers, Environ.ment 1: 83-96
individuals was 2.4%, compared to an retailers, writers, researchers, 0 Miller, E. C. et al. (1983)
average of 15% in those with skin teachers or practitioners, we all need Structure-activity studies of the
colour described as dark brown or to increase our knowledge of carcinogenicities in the mouse and
black (Zaynoun et al., 1977). A suntan essential oil safety. I believe this rat of some naturally occurring and
gave light skin some extra protection. subjecl should not be regarded as synthetic alkenylbcnzene derivatives
something for so-called ‘advanced relaled to safrole and estragole.
When there is an increased risk of training courses’ it should be basic to Cancer Research 43: 1124-l 134
phototoxicity any serious aromatherapy training. 0 Taylor, J. M. et al. (1967)
There are LWO scenarios in which the Toxicity of oil of calamus (Jammu
risk of phototoxicity may be increased. Essen.tial Oil Safety, by Robert Tisserand variety). ToxicoloSq and A$plied
Firstly, if several phototoxic oils are and ?&1y Balacs, is published Pharmecology 10: 405
used together, the risk increases by s Ch.urchill Livin,gstone, 0 Vesselinovitch, S. D. et al.
proportionally. For instance, if ISBN: 0443 052h0 3. (1979) Transplaccntal and lactational
bergamot and cumin oils are both used carcinogenesis by safrolc. Cancer
in a product in equal proportions, the Research 39: 4378-4380
maximum safe percentage will be 0.2% 0 Wiseman. R. W. et al. (1987)
for each, not 0.4% for each. Structure-activity studies of the
Secondly, if concentrated 0 Abbot, D. D. et al. (1961) hepatocarcinogenicities of alkenyl-
(deterpenated) citrus oils are used, the Chronic oral toxicity of oil of sassafras benzene derivatives related to
maximum percentage 01 essential oil and safrol. Pharmacologist 3 (73) : 62 estragole and safrole on
should be reduced in proporlion to the 0 Anon (1992) Lemon burn administration to preweanling male
degree of concentration. Citrus oils warning. lnternation.al ,Journal q/ mice. Cancer Research 47: 2275-2283
generally contain a large Aromatherafiy 4 (4) :4 0 Zangouras, A. et al. (1981)
amount of terpcnes. Deterpenated 0 Caporale, G et al. (1967) Dose-dependent conversion of
(rdeterpenised, terpenelcss, or Skin photosensitizing activily of some estragole in the rat and mouse to the
tcrpcncfree) citrus oils therefore methylpsoralens. Exfiewntia 23: 985 - carcinogenic metabolite l’-
possess all their other components 986 hydroxyestragole. Biochemical
(including the furanocoumarins) in 0 Drinkwater, N.R. et al. Pharmacology 30: 1383-1386
much larger amounts. So, a 10 times (1976) Hcpatocarcinogenicity ?? Zaynoun, S. T. el al. (1977) A
concentrated expressed lemon oil will of cstragole (1.allyl-4- study of bcrgamot and its importance
have a maximum safe ConcenlraLion of methoxybenzenc) and l’-hydro- as a phototoxic agent. Contact
0.2%, instead of 2%. xyestragole in the mouse and Dermatitis 3: 225-239