View
218
Download
1
Embed Size (px)
Citation preview
7/30/2019 guaiacol_toxicity.pdf
1/2
Proc. West. Pharmacol. Soc. 52: 92-93 (2009)
Acute Toxicity of Guaiacol Administered Subcutaneously in the Mouse
Maria Elena Martnez Enriquez1, Andrea Del Villar
1, David. Chauvet
1, Alfredo Lopez Valle
2,
Macario Susano Pompeyo2
and Alfonso Efran Campos Seplveda1.
1Departamento de Farmacologa, Facultad de Medicina, Universidad Nacional Autnoma de Mxico,
2Servicio Mdico
Forense del Tribunal de Justicia del DF, MxicoE-mail:[email protected]
AbstractGuaiacol is a compound used as expectorant. In Mexico City, this product is being illegally used for aesthetic
treatment with fatal results. The aim of this study is to confirm the lethal toxicity documented in humans. Male
Swiss Webster mice (CFW) 30-45g were employed. Doseresponse curves to guaiacol were performed by
subcutaneous administration (6.25-400 l/40g). Basal temperature was recorded 30120 min following
administration of guaiacol. Animals were continuously observed for 120 min after guaiacol administration,
lethality and toxicity manifestations were recorded. Depending of the dose, high toxicity was observed; sub
lethal doses (6.25-12.5 l/40 g) produced tachycardia and hyperactivity, follow by sedation, hypnosis, high
hypothermic effect (loss of 6C) dyspnea, myoclonus, hematuria, blindness, abdominal distension and in higher
doses (25-400 l/40 g) lethal effect. Necropsy showed hepatic and renal necrosis, pulmonary edema,
hemorrhages and bladder clotting. We concluded that guaiacol is an extremely toxic product (toxic rating class
5) whose use should be restricted or banned.
Introduction
Guaiacol (o-metoxyfenol; metilcatecol; 2-metoxifen-
ol) is a phenolic natural compound that is isolated
from the resin ofGuiacum officinale, plants belonging
to the family ofZygophyllaceae [1]. The compound
can also be obtained from the creosote product of the
distillation of vegetal tar obtained from wood (Fagus
selvatica) [2]. This compound is used in the clinic as an
expectorant, antiseptic and with local anesthetic [3] In
preparation of food by smoking, guaiacol is the mainchemical responsible for the smoky taste. As an
expectorant, it increases secretions of the respiratory
tract by liquefying mucous secretions. The reported
lethal dose by oral route in humans is 50 mg/kg and
the adverse reactions caused by the consumption of
this compound are gastrointestinal malaise and in
high dose, nauseas and vomiting [2,4].
Information that guaiacol is being used irrationally
and clandestinely with aesthetic aims as surfaced.
Some have employed it by the subcutaneous route to
improve body contour. Guaiacol can cause
neurological, hemodynamic (shock), respiratory,
metabolic (metabolic acidosis), renal (acute tubular
necrosis), digestive and hematologic adverse effects.
Acute pulmonary edema precedes death by multiple
organic failure [5]. The aim of this work was to
confirm experimentally in the mouse, the toxicity
reported in humans, by testing the subcutaneous
administration of pure Guaiacol .
Methods
Male and female adult mice of, 30-40 g of weight, from ourbreeding facilities (CFW strain, obtained from Taconic Farm,
Germantown, NY) were used. Dose-response curves to the
toxicity of guaiacol was carry out at six doses of pure
guaiacol (6.25, 12.5, 25, 50, 100 and 200 l, by
subcutaneous route); six to seven mice by dose. The control
group was injected with saline solution. In all cases the
basal rectal temperature was continuously recorded (Tele-
Thermometer YSI-44TA) at 30, 60 and 120 minutes after the
administration of the drug. The manifestations of toxicity
were observed and the lethality measured for four hr
following treatment. Observational measurements of
straightening reflex and blindness, tachycardia, dyspnea
were documented by inspection. Hemorrhage, hepaticnecrosis and pulmonary edema were determined by
necropsy.
The studies have been carried out in accordance with the
Declaration of Helsinki and with the Guide for Care and Use
of Laboratory Animals as adopted and promulgated by the
U.S. National Institute of Health.
Statistical analysis was carried out by one-way analysis of
variance (ANOVA) with Students t-test and Chi-square test.
Statistic significance was set at p< 0.05.
Results and Discussion
The manifestations of toxicity displayed by animalsthat received doses of 12.5 to 200 l of pure guaiacol
were: gastric distention, hematuria and hepatic
necrosis. These manifestations of toxicity were
pronounced in 100% of animals; pulmonary edema
appeared in 87.5% and unilateral or bilateral
blindness in 62.5% of mice. Furthermore, non-specific
abdominal hemorrhaging was commonly observed at
necropsy. Following these doses of guaiacol, 100% of
the animals died in the first 60 minutes. With
sublethal doses (6.25 l) the mice displayed dyspnea
in the first minutes, sedation, hypnosis, myoclonus,abdominal distention, hematuria, tachycardia and
blindness (unilateral or bilateral).
http://localhost/var/www/apps/conversion/tmp/scratch_9/[email protected]://localhost/var/www/apps/conversion/tmp/scratch_9/[email protected]://localhost/var/www/apps/conversion/tmp/scratch_9/[email protected]://localhost/var/www/apps/conversion/tmp/scratch_9/[email protected]7/30/2019 guaiacol_toxicity.pdf
2/2
Proc. West. Pharmacol. Soc. 52: 92-93 (2009)
The time course of the hypothermic effect of guaiacol
in high doses (50, 100 and 200 l; Fig 1) is offered as a
general surrogate for the toxic effects of guaiacol and
demonstrates that the rectal temperature diminishes
significantly (p < 0.05) quite rapidly depending on
dose. The average temperature decreased 6.3C in 60
min at higher doses. In low doses (6.25 and 12.5 l),the hypothermic effect is less intense, with tendency
to stabilize at the lower temperature.
Figure 1. Time course of dose-response curve to the
hypothermic effect induced by acute administration of
Guaiacol in mice. Results are expressed as average E.E.
of rectal temperature. Each point n= 6 to 7 animals. Data
are significant for the each dose compared to control as
shown, p< 0.05.
The lethal dose fifty percent (LD50) of guaiacol
administered by the subcutaneous route is between
6.25 and 12.5 l. The results of this study indicate that
guaiacol is an extremely toxic substance (Toxic Rating
Class 5; see ref. 7). Available information indicates
that guaiacol produces nausea, vomiting, diarrhea,
gastrointestinal and respiratory irritation as adverse
reactions [2,6,7].
Also guaiacol in high concentrations is known to bring
about adverse effects similar to that which appears as
a result of poisoning with phenol, but of decreased
severity. Phenol produces depression of the centralnervous system, cardiac arrhythmias, disturbance
circulatory and respiratory that can lead to death.
Guaiacol can produce acidosis, hemolysis and
methemoglobinemia with cyanosis [8].
The severe manifestations of toxicity observed in the
animals that received guaiacol subcutaneously are
likely due to the close structural relationship between
phenol and guaiacol. Moreover, a related compound,
guaifenesin (glyceryl guaiacolate); a drug used as
anticongestive, expectorant and muscular relaxant in
veterinary medicine produces similar toxic effects.Acute overdose (110 mg/kg, iv) or in high
concentrations 5%, induce hemolysis, hypotension
and hypoxaemia [8]. We conclude that guaiacol is an
extremely toxic compound, for this reason the use of
this drug must be restricted or banned from use.
References
1. Dorfner, R., Ferge, T., Kettrup, A., Zimmermann, R.,Yeretzian, C. (2003) J. Agri. Food. Chem. 51(19): 5768
73.
2. Diccionario de Especialidades Farmacuticas. 54thEdicin, Mxico: Thomson. PLM, S. A. de C. V., 2008:
1538.
3. Sasagawa, T., Ehara, M., and Maizumi, H. (1985) Localanesthetic effect of phenol derivatives. 2. Eugenol and
guaiacol. In Shigaku-Odontology, 73(1):52-66.
4. Orlowski, J., Boruszak, D. (1991) Fol. Med. Cracov. 32,309-317.
5. Gonzlez, M.D., Ibarra, G. (1988) Rev. Med. Hosp. Gen.Mex. 61, 163-165.
6. Merck Index 13th Edition, Rahway, New Jersey.,2001:4568.
7.
Gosselin, RE., Hodge, HC., Smith, RP., Gleason, MN.Clinical Toxicology of Commercial Products. Acute
Poisoning. 4a. ed. Williams and Wilkins, 1981:1-4
8. Islas, P., Valenzuela, J., Jerardino, M., Mayer, H. (1987)Rev. Chil. Pediatr.58(5); 402-404.
9. Anon: Fed. Regist. 1989; 54(38):8494-509.
20
25
30
35
40
0 30 60 120
T I M E (min)
RECT
ALTEMPERATUREC
Control 12.5 l 25 l 50 l
http://openwindow%28520%2C%20450%2C%20%27http//www.imbiomed.com.mx/1/1/autores.php?method=listArticlebyAuthor&id_revista=29&id_autor=20464%27)http://openwindow%28520%2C%20450%2C%20%27http//www.imbiomed.com.mx/1/1/autores.php?method=listArticlebyAuthor&id_revista=29&id_autor=7748%27)http://openwindow%28520%2C%20450%2C%20%27http//www.imbiomed.com.mx/1/1/autores.php?method=listArticlebyAuthor&id_revista=29&id_autor=7748%27)http://openwindow%28520%2C%20450%2C%20%27http//www.imbiomed.com.mx/1/1/autores.php?method=listArticlebyAuthor&id_revista=29&id_autor=20464%27)