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Toxicity and medical use
REPLY TOXICITY/MEDICAL USE

REPORT ON THE DEVELOPMENT OF NEW INSIGHTS INTO THE MEDICINAL USE OF JOJOBA


Initial insights

Many decades ago, farmers in the US tried to use the worthless, residual oil-containing jojoba press cake (obtained after expressing the oil) as life stock cattle feed. High doses of press cake (up to 50%) were added to chopped corn. Instead of gaining weight, the animals started to emaciate and finally died, although the examined nutritional value seemed to be all right. There was, obviously, a serious problem.

Next, different feed formulations were tested by mainly university institutes. The general purpose of these research attempts was to achieve more knowledge about the use of the worthless jojoba press cake or meal as livestock feed or as food supplement. A review by Jaime Wisniak (1987) is fully dedicated to the preparation and possible use of jojoba meal.

The common ‘scientific’, but unproven idea was to classify the simmondsins, the most important secondary metabolites present in jojoba, as toxic agents that should be eliminated through chemical manipulations.

After a detailed study of the scientific literature from 1970 until 1987 about jojoba and its constituents (174 papers), contradictory results and vague conclusions were evident, while practical jojoba meal applications had not emerged yet.


Further research

Intrigued by the lack of clear insights into the potencies of jojoba in general and simmondsins in particular, we set up an industrial partnership with the Catholic University of Leuven (KUL). Late September 1987, I ordered a study to find out whether or not simmondsins are toxic and, if so, to what extent? Prof. Dr. Cokelaere (Laboratory of Toxicology and Food Chemistry) received 20 g dimethylsimmondsins (> 95% pure) from Prof. Dr. Ralph Price (University of Tucson, Arizona, USA). The outcome was quite clear: no toxicity could be found in adult rats, not even when a single massive dose was administered (4 g/kg BW). In addition, the researchers not only disapproved the toxicity, but they revealed a strong inhibition on the intake of food. This study is still in progress. However, in 1993, due to a conflict situation, whereby KUL lost a patent, I dismissed and continued on my own.

The follow-up of the KUL publications made also clear to us that this group continued along the same lines without understanding the underlying basic principles that could possibly explain some specific observations (Vermaut et al., 1998). Therefore, Mr. S. Raes and myself started to suspect that there was a lot more going on than just ‘food intake inhibition’.


Breakthrough

In 1994, I started to work as a free-lance investigator at the Ghent University, first at the Laboratory of Plant Biochemistry (Prof. Dr. C. Van Summere & Dr. L. De Cooman) for a period of 30 months. Afterwards I moved to the Laboratory of Organic Chemistry – Separation Techniques (Prof. Dr. P. Sandra) where I continued to work until 2005. The objective of the study remained to ameliorate techniques to de-oil the jojoba press cake more efficiently and to remove the peel fragments (since the para-coumaric acids present provoked a bitter taste). This resulted in refined, de-oiled jojoba meal that allowed more efficient simmondsins isolation. Following our route, the simmondsins could be fractionated into their distinct components for further individual testing.

Late 2000, we decided to conduct some in vivo tests. I had chosen to engage Prof. Dr. M. Mareel (Laboratory of Experimental Cancerology, UZ Gent) to perform a CAM-test on fertilized eggs. In addition, we also contracted TNO (Leiden) to perform a series of in vitro and in vivo tests, while at the same time continuing our own in vivo experiments on balb/c mice.

All results, described in our report by A. D’Oosterlynck & S. Raes, “Use of Simmondsin as an Angiogenesis Inhibitor” (2008), confirmed our hypothesis that all simmondsins and homologues - and also the refined jojoba meal in which these molecules are present - are very strong inhibitors of angiogenesis. These results are meanwhile also protected by patent (D’Oosterlynck, 2003).


Conclusion

The supposed toxicity of the simmondsins administrated to mostly young, fast growing animals is presented here. Death through starvation is obvious, but this can hardly be considered as toxic. Dimethylsimmondsin and its homologues are not suited as appetite suppressants nor as nutritional additives. The strong angiogenesis inhibiting effects of all simmondsins are not compatible with food as such, but should be regarded as a medicine.

Based upon an article of Flo et al. (1998), in which - without any motivation - is postulated that solely dimethylsimmondsin has food intake inhibitive properties and all other simmondsins have not, some vendors in the US are selling simmondsins as appetite suppressants (see some attached commercialized appetite suppressant formulations, which are also available in Europe when ordering from the internet). The problem is that these products are sold without warning for the “unidentified factors”, but we know them as angiogenesis inhibiting agents, which are in fact covered by my patent application (D’Oosterlynck 2003).

In Europe, the regulation of food additives and supplements is more severe; see the innocent (or ignorant) reaction of the German Ministry of Public Health (BfR, Nr. 012/2007) . Unfortunately, they refer to an old publication by Booth et al. (1974) in which Sprague-Dawley rats were fed with 750 mg simmondsins/kg BW/day. All animals died within 10 days but autopsy failed to reveal any gross abnormalities, thus excluding toxicity. Production of HCN was suspected, because of the presence of the nitrile group on the hexyl ring of the simmondsins. The release of HCN is fully unjustified, as most wrongly inspired by Elliger et al. (1973). See also the declaration by Prof. Dr. D. De Keukeleire (2009), Honorary-full Professor Ghent University, Belgium (in annex).

Using a dose of 750 mg/Kg BW/day, it is no surprise that these animals died quite soon of starvation. These young, fast growing animals were simply killed by non-nutrition, while they where badly influenced by a super dose of a potent angiogenesis inhibitor at the same time. Based upon our research results, we recommend simmondsins only to adults, at a dose of only 2 to max. 10 mg simmondsins/Kg BW/day for angiogenesis related diseases, which is far (a couple of hundred times) less than the described dose of 750 mg of Booth et al. (1974). Since every administered compound – albeit a medicine or a food additive – has it’s own daily allowances, we can only conclude that the German directive Bfr. 012/2007 has based its report on outdated and wrong information in their attempt to refuse jojoba meal or simmondsins as a food additive.

In general, we may conclude that simmondsins are not suited as appetite suppressant, but have a very high value as an angiogenesis inhibitor, i.e. a food additive with medicinal value or a medicine for the treatment of diseases such as Rheumatoid Arthritis and even cancer resp.



Legend


PC: Jojoba press cake still containing up to 13% residual oil.

DJM: de-oiled (using hexane) jojoba press cake or de-oiled jojoba meal.

S’n: Simmondsins total polar extract.

S: Dimethylsimmondsin - appetite suppressant as found by KUL.

DMS: 4- & 5-Desmethylsimmondsins (2 isomers).

DDMS: Didesmethylsimmondsin.


Note 1 : All simmondsins are also present as cis-trans ferulates.

Note 2 : DJM contains, depending on plant type and growing zone, approx. 5% S and 6-7% homologues.


Addendum


A selection of 13 scientific publications (abstracts from NERAC) dealing with ‘appetite suppression’ with special attention to the ‘toxicity’ of the simmondsins is added.

Nerac, Research Report on Simmondsin: Report Number 08685749-1 November 30, 2005.

A small comment is added to some of these publications.


(1) Publication 3: Arnouts et al. (1993)

Conclusion: young pullets were fed 3-5 weeks on diets containing 0 and up to 12% jojoba meal (DJM), i.e., more than 1000 mg/kg body weight. No mortality is being reported. LD 50 unknown.


(2) Publication 5: Cokelaere et al. (2000)

Conclusion: Feeding up to 20 weeks demonstrated no microscopic nor biochemical sign of toxicity.


(3) Publication 8: Lievens et al. (2003)

Conclusion: Up to 0.5% pure S revealed no toxicity in adult rats. Estimated daily feed consumption: 20 g. Individual average body weight: 350 g. Equals to 250 mg S/kg body weight.


(4) Publication 10: Ham et al. (2000)

Conclusion: Dogs (adult, 2-8 years old Beagle) supplemented with up to 8,1% DJM, equivalent to approximately 1% total simmondsins (S'n), revealed no toxicity. Average body-weight: 15 kg, daily consumption test feed: 300 g, equals: 200 mg/kg body weight.

 

(5) Publication 17: Wang et al. (2003a)

Jojoba product for reducing weight, blood lipid levels and for the prevention and treatment of cancer (Patent 2003-08-07).

Conclusion: in conflict with Priority Belgian patent 2002/ 0428, July 8, 2002, registered in Belgium 8 July 2001 .


(6) Publication 23: Cokelaere et al. (1992)

Conclusion: 250 mg pure simmondsin (S)/kg body weight did not have any toxic influences on liver, pancreas and kidneys using several biochemical parameters. Anatomopathological investigation of kidney, liver, pancreas, stomach, intestine, testis, and seminal vesicle also did not demonstrate any pathological change. There are no indications that HCN is being produced.

See also the declaration by Prof. Dr. D. De Keukeleire, Honorary-full Professor Ghent University, Belgium.


(7) Publication 24: Flo et al. (1999)

Conclusion: Feed supplemented with 2.5 g simmondsin (S)/kg feed or 0.25% demonstrated no toxicity in long-term tests.


(8) Publication 27: Wang et al. (2003b)

Notes:

1. Weight loss or losing fat by the use of simmondsins is no more protected by a patent since 1992.

2. The use of simmondsins as an angiogenesis inhibitor is being patented in Belgium since 2001-07-08.


(9) Publication 28: Vermaut (1998)

Notes:

1: “Anti-nutritional factors (?) in jojoba meal probably have a negative effect on digestibility and growth in poultry.”

2: “Totally unexpected, these -jojoba treated- breeders never produced eggs. Jojoba meal apparently hampers oviduct growth. This is probably due to some, yet unidentified factors in the meal.”

Comment:

Since 1993, no progress has been made in the understanding and the insight of the bioactivities of the simmondsins. The presence of simmondsin homologues other than dimethylsimmondsins seems neglected, despite the fact they are predominant in the jojoba meal. These ‘neglected’ molecules (+/- 10) do not show any activity on food intake inhibition, but evidently on another biological level (see also: Flo et al. (1998) vs. our Personal research report (2007))


(10) Publication 33 : Cokelaere et al. (2001)

Conclusion: no toxicity observed.


(11) Publication 34 : Ngoupayou et al. (1982)

Tests with untreated jojoba meal, containing 4.7% S and at least the same amount of DMS and DDMS.

Conclusion: Important article since it defines and modifies the hypothesis that simmondsins are “toxicants”.


(12) Publication 36: York et al. (2000)

Comment:

Long-term feeding with 0.5% S supplemented food led to “profound weight loss and dead in rats”.

Calculation:

Weight of a male Sprague-Dawly rat: 380 g.

Daily food intake : 15 g.

Daily S intake : = (15 x 0.5%): 100 = 0.075g = 75 mg.

Daily S intake/kg body weight (BW) = (75 x 1000) : 350 = 200 mg/kg BW/day.

Prolonged feeding with such high amount of S leads to extreme emaciation most likely resulting in death.

On the one hand, animals die due to a chronic treatment of 200 mg/kg BW/day during several months; on the other hand, an acute overdose of more than 6000 mg/kg BW does not show any consequence at all.

FYI : we use simmondsins in humans for inhibition of angiogenesis at a dose of 2-10 mg/ kg BW/day.


(13) Publication 38: Manos et al. (1986)

Conclusion: pp. 803-804: lambs, 3 months old, of the Dorset breed. Average test duration, 48 and 80 days, respectively. Feed supplemented with 5 and 10 % 'jojoba meal’ did not demonstrate any toxicity.


Reference list (Publications marked with *** are available as full copy).


*** Arnouts S., Buysse J., Cokelaere M.M. and Decuypere E. Jojoba meal (Simmondsia chinensis) in the diet of broiler breeder pullets: physiological and endocrinological effects Poultry Science (1993) 72 (9):1714-1721.

*** Bfr. Jojobasamen sind nicht für den Verzehr geeignet. Information Nr. 012/2007 des BfR vom 12. März 2007.

*** Booth A.N., Elliger C.A., Waiss Jr. A.C. Isolation of a Toxic factor from jojoba meal. Life Sci. (1974) 15:1115-1120.

*** Cokelaere M., Dangreau H.D., Daenens P., Bruneel N., Arnouts S., Decuypere E. and Kuhn E.R. Investigation of possible toxic influences of simmondsin after subacute administration in the rat. Journal of Agricultural and Food Chemistry (1992) 40:2443-2445

* Cokelaere M., Cauwelier B., Cokelaere K., Flo G., Houache N., Lievens S., Van Boven M. and Decuypere E Hematological and pathological effects of 0.25 % purified simmondsin in growing rats. Industrial Crops and Products. (2000) 12:165-171.

* Cokelaere M., Flo G., Lievens S., Van Boven M., Vermaut S. and Decuypere E. Teratological Studies in defatted jojoba meal-supplemented rats. Food and Chemical Toxicology (2001) 39(3):247-252

*** De Keukeleire D. (2009) Personal email communication dd. 12 oct 2009

*** D’Oosterlynck A. Patent Application 2002/0428. Filed on July 8, 2002; registered in Belgium 8 July 2001.

*** D’Oosterlynck A. Simmondsin as an Angiogenesis inhibitor (2003) EPO3/07270; US7387999 granted june 17th 2008.

*** D’Oosterlynck A. and Raes S. The effect of Simmondsin derivates. (2007) Own study report. Pp 1-101.

* Elliger C.A., Waiss Jr. A.C. and Lundin R.E. J. Chem. Soc. Perkin (1973) 1:2209-2213.

* Ham R., Vermaut S., Flo G., Cokelaere M. and Decuypere E. Digestive performance of dogs fed a jojoba meal supplemented diet. Industrial Crops and Products (2000) 12(3):159-163.

*** Flo G., Vermaut S., Darras V.M., Van Boven M., Decuypere E., Kuhn E.R., Daenens P. Cokelaere M. Effects of simmondsin on food intake, growth and metabolic variables in lean (+/?) and obese (fa/fa) Zucker rats. British Journal of Nutrition (1999) 81:159-167.

*** Flo G., Van Boven M., Vermaut S., Decuypere E., Daenens P. and Cokelaere M. Effect of simmondsin derivatives on food intake: dose-response curves in rats. J. Agric. Food Chem. (1998) 46:1910-1913.

* Lievens S., Flo G., Decuypere E., Van Boven M., Cokelaere M. Simmondsin: effects on meal patterns and choice behaviour in rats. Physiol. Behaviour (2003) 78:669-677 *** Manos C.G., Schrynemeecker P.J., Hogue D.E., Telford J.N., Stoewsand G.S., Beerman D.H., Babish J.G. Blue J.T., Shane B.S. and Lisk D.J. Toxicologic studies with lambs fed jojoba meal supplemented rations. Journal of Agriculture and Food Chemistry. (1986) 34:801-805

* Ngou Ngoupayou J.D. Nutritional evaluation of Jojoba meal. (1982) 43.

* Vermaut S. Jojoba meal as an additive in poultry feed: effect on feed intake, growth and reproduction. (1998) 60.

*** Vermaut S., Onagbesan O., Bruggeman V., Verhoeven G., Berghman L., Flo G., Cokelaere M. and Decuypere E. Unidentified Factors in Jojoba Meal prevent Oviduct Development in Broiler Breeder Females. Journal of Agriculture and Food Chemistry (1998) 46:194-201.

* Wang Y., Wang Y. and Reilly P. Jojoba product for reducing weight, blood lipid levels and for the prevention and treatment of cancer. (2003a) EP1480613

* Wang Y., Reilly P. and Wang Y. Preparation and administration of jojoba product for reducing weight, fat and blood lipid levels and for the prevention and treatment of cancer (2003b) US Patent 7138134.

* Wisniak J. The Chemistry and Technology of Jojoba Oil. in : The American Oil Chemist’s Society. (1987) pp 213-250.

* York D.A., Singer L., Oliver J., Abbott T.P., Bray G.A. The detrimental effect of simmondsin on food intake and body weight of rats. Industrial Crops and Products (2000) 12:183-192.


ANNEX:


TO WHOM IT CONCERNS

Simmondsins derived from
Simmondsia chinensis (Link) C. K. Schneider are not cyanogens, because the cyano group can not be eliminated as hydrogen cyanide by lack of a hydrogen atom in alpha position (the alpha carbon atom is tetra-substituted).

Prof. Dr. Denis De Keukeleire
Honorary-full Professor Universiteit Gent




 



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