World Health Organization: In experimental animals trichothecenes were 40 times more toxic when inhaled than when given orally

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Repeated, intentional, glaring omission in ACOEM, AAAAI, CDC, EPA

publications... however, its mentioned in...

(WHO) Bulletin of the World Health Organization, 1999, 77(9) p759

" Toxic effects of mycotoxins in humans "

quote: " In experimental animals trichothecenes were 40 times more

toxic when inhaled than when given orally "

http://whqlibdoc.who.int/bulletin/1999/Vol77-No9/bulletin_1999_77(9)_754-766.pdf

(for full text)

Toxic effects of mycotoxins in humans

M. Peraica,1 B. Radic¬ ,2 A. Lucic¬ ,3 & M. Pavlovic¬ 4

1 Toxicologist, Unit of Toxicology, Institute for Medical Research and

Occupational Health, Ksaverska cesta 2, POB 291, HR-10001 Zagreb,

Croatia.

2 Toxicologist, Head of Unit of Toxicology, Institute for Medical

Research and Occupational Health, Zagreb, Croatia.

3 Toxicologist, Unit of Toxicology, Institute for Medical Research and

Occupational Health, Zagreb, Croatia.

4 Pulmonologist, Department of Occupational and Environmental

Health, Institute for Medical Research and Occupational Health,

Zagreb, Croatia.

Research

Abstract:

Mycotoxicoses are diseases caused by mycotoxins, i.e. secondary

metabolites of moulds. Although they occur more

frequently in areas with a hot and humid climate, favourable for the

growth of moulds, they can also be found in

temperate zones. Exposure to mycotoxins is mostly by ingestion, but

also occurs by the dermal and inhalation routes.

Mycotoxicoses often remain unrecognized by medical professionals,

except when large numbers of people are

involved. The present article reviews outbreaks of mycotoxicoses where

the mycotoxic etiology of the disease is

supported by mycotoxin analysis or identification of

mycotoxin-producing fungi. Epidemiological, clinical and

histological findings (when available) in outbreaks of mycotoxicoses

resulting from exposure to aflatoxins, ergot,

trichothecenes, ochratoxins, 3-nitropropionic acid, zearalenone and

fumonisins are discussed.

Introduction

Mycotoxins are secondary metabolites of moulds that

exert toxic effects on animals and humans. The toxic

effect of mycotoxins on animal and human health is

referred to as mycotoxicosis, the severity of which

depends on the toxicity of the mycotoxin, the extent

of exposure, age and nutritional status of the

individual and possible synergistic effects of other

chemicals to which the individual is exposed. The

chemical structures of mycotoxins vary considerably,

but they are all relatively low molecular mass organic

compounds.

The untoward effect of moulds and fungi was

known already in ancient times (1). In the seventh and

eighth centuries BC the festival ``Robigalia'' was

established to honour the god Robigus, who had to

be propitiated in order to protect grain and trees. It was

celebrated on 25 April because that was the most likely

time for crops to be attacked by rust or mildew (2).

In the Middle Ages, outbreaks of ergotism

caused by ergot alkaloids from Claviceps purpurea

reached epidemic proportions, mutilating and killing

thousands of people in Europe. Ergotism was also

known as ignis sacer (sacred fire) or St 's fire,

because at the time it was thought that a pilgrimage to

the shrine of St would bring relief from the

intense burning sensation experienced. The victims

of ergotism were exposed to lysergic acid diethylamide

(LSD), a hallucinogen, produced during the

baking of bread made with ergot-contaminated

wheat, as well as to other ergot toxins and

hallucinogens, as well as belladonna alkaloids from

mandragora apple, which was used to treat ergotism

(3). While ergotism no longer has such important

implications for public health, recent reports indicate

that outbreaks of human mycotoxicoses are still

possible (4).

Some mycotoxicoses have disappeared owing

to more rigorous hygiene measures. For example,

citreoviridin-related malignant acute cardiac beriberi

(``yellow rice disease'' or shoshin-kakke disease in

Japanese) has not been reported for several decades,

following the exclusion of mouldy rice from the

markets. Citreoviridin is a metabolic product of

Penicillium citreonigrum, which grows readily on rice

during storage after harvest (5), especially in the

colder regions of Japan (6). Another mycotoxicosis

not seen for decades is alimentary toxic aleukia,

common in the 1930s and 1940s in the USSR. This

disease was caused by trichothecenes produced by

Fusarium strains on unharvested grain.

General interest in mycotoxins rose in 1960

when a feed-related mycotoxicosis called turkey X

disease, which was later proved to be caused by

aflatoxins, appeared in farm animals in England.

Subsequently it was found that aflatoxins are hepatocarcinogens

in animals and humans, and this

stimulated research on mycotoxins.

There is a long history of the use of certain

moulds in the production of cheese and salami and in

the fermentation of beer and wine. Moulds are also

used in the production of drugs (antibiotics). The

classification of mould metabolites as antibiotics or

mycotoxins is based on their toxicity or beneficial

effect in treating diseases. Some mould metabolites

that were initially considered to be antibiotics (e.g.

citrinin) were subsequently found to be highly toxic

(7), and are currently classified as toxins. Ergot

alkaloids are still used, inter alia, in the treatment of

parkinsonism, as prolactin inhibitors, in cerebrovascular

insufficiency, migraine treatment, venous

insufficiency, thrombosis and embolisms, for the

stimulation of cerebral and peripheral metabolism, in

uterine stimulation, as a dopaminergic agonist (8).

The toxic effects of mycotoxins (e.g. ochratoxins,

fumonisins, zearalenone, etc.) are mostly known

from veterinary practice. Mycotoxicoses, which can

occur in both industrialized and developing countries,

arise when environmental, social and economic

conditions combine with meteorological conditions

(humidity, temperature) which favour the growth of

moulds.

Involvement of mycotoxins in disease causation

should be considered in instances when a disease

appears in several persons, with no obvious connection

to a known etiological agent, such as microorganisms.

Given current trade patterns, mycotoxicoses

resulting from contaminated food, locally

grown or imported, could occur in developing and

developed countries alike. Strict control of food and

feed and appropriate public health measures are

therefore of considerable importance in reducing the

risks to human and animal health.

This review covers only the human aspects of

the untoward effects of mycotoxins. However,

owing to the frequent nonspecific effects of

mycotoxin involvement, the results of animal

experiments are useful for understanding possible

effects on humans. Since review articles and books

are available dealing with specific topics such as the

chemistry, analytical procedures, metabolism, and

economic aspects of mycotoxins (9±18), these

aspects of mycotoxin toxicology are not presented

here. Mycotoxicoses are usually insufficiently treated

in medical textbooks and are not covered in curricula

of many medical schools. The aim of this article is to

summarize current understanding of the clinical

aspects mainly of mycotoxicoses in humans, and to

stress the importance of this class of naturally

occurring toxins.

Ergot

Ergot is the common name of the sclerotia of fungal

species within the genus Claviceps, which produce

ergot alkaloids. The sclerotium is the dark-coloured,

hard fungal mass that replaces the seed or kernel of a

plant following infestation. Ergot alkaloids are also

secondary metabolites of some strains of Penicillium,

Aspergillus and Rhizopus spp. (8).

The ca. 40 ergot alkaloids isolated from

Claviceps sclerotia can be divided into three groups:

± derivatives of lysergic acid (e.g. ergotamine and

ergocristine);

± derivatives of isolysergic acid (e.g. ergotaminine);

± derivatives of dimethylergoline (clavines, e.g.

agroclavine) (12).

The source of the ergot strongly influences the type

of alkaloids present, as well as the clinical picture of

ergotism (19).

Claviceps purpurea produces ergotamine-ergocristine

alkaloids, which cause the gangrenous form

of ergotism because of their vasoconstrictive activity.

The initial symptoms are oedema of the legs, with

severe pains. Paraesthesias are followed by gangrene

at the tendons, with painless demarcation. The lastrecorded

outbreak of gangrenous ergotism occurred

in Ethiopia in 1977±78; 140 persons were affected

and the mortality was high (34%) (20).

The other type of ergotism, a convulsive form

related to intoxication with clavine alkaloids from

Claviceps fusiformis, was last seen during 1975 in India

when 78 persons were affected (21, 22). It was

characterized by gastrointestinal symptoms (nausea,

vomiting and giddiness) followed by effects on the

central nervous system (drowsiness, prolonged

sleepiness, twitching, convulsions, blindness and

paralysis). The onset of symptoms occurred 1±48

hours following exposure; there were no fatalities.

Ergotism is extremely rare today, primarily

because the normal grain cleaning and milling

processes remove most of the ergot so that only

very low levels of alkaloids remain in the resultant

flours. In addition, the alkaloids that are the causative

agents of ergotism are relatively labile and are usually

destroyed during baking and cooking.

Aflatoxins

Aflatoxins occur in nuts, cereals and rice under

conditions of high humidity and temperature and

present a risk to human health that is insufficiently

recognized. The two major Aspergillus species that

produce aflatoxins are A. flavus, which produces only

B aflatoxins, and A. parasiticus, which produces both

B and G aflatoxins. Aflatoxins M1 and M2 are

oxidative metabolic products of aflatoxins B1 and B2

produced by animals following ingestion, and so

appear in milk (both animal and human), urine and

faeces. Aflatoxicol is a reductive metabolite of

aflatoxin B1 .

Aflatoxins are acutely toxic, immunosuppressive,

mutagenic, teratogenic and carcinogenic compounds.

The main target organ for toxicity and

carcinogenicity is the liver. The evaluation of

epidemiological and laboratory results carried out in

1987 by the International Agency for Research on

Cancer (IARC) found that there is sufficient evidence

in humans for the carcinogenicity of naturally

occurring mixtures of aflatoxins, which are therefore

classified as Group 1 carcinogens, except for

aflatoxin M1, which is possibly carcinogenic to

humans (Group 2B) (23).

Several outbreaks of aflatoxicosis have occurred

in tropical countries, mostly among adults in

rural populations with a poor level of nutrition for

whom maize is the staple food (Table 1). The clinical

picture presented by cases indicated acute toxic liver

injury, which was confirmed by morphological

changes in liver autopsy specimens that were

indicative of toxic hepatitis (27). Mortality rates in

the acute phase were 10±60 %. At the end of one year,

surviving patients had no jaundice, and most of them

had recovered clinically (26).

A case of attempted suicide with purified

aflatoxin B1 is reported to have occurred in 1966 in

the USA (29). A young woman ingested a total of

5.5 mg of aflatoxin B1 over 2 days and, 6 months

later, a total of 35 mg over 2 weeks. Following the first

exposure, she was admitted to hospital with a

transient, nonpruritic, macular rash, nausea and

headache; the second time she reported nausea only.

On both occasions, physical, radiological and

laboratory examinations were normal and liver

biopsies appeared normal by light microscopy. A

follow-up examination 14 years later did not reveal

any signs or symptoms of disease or lesions. These

findings suggest that the hepatotoxicity of aflatoxin

B1 may be lower in well nourished persons than in

experimental animals or that the latent period for

tumour formation may exceed 14 years.

Aflatoxins have been detected in the blood of

pregnant women, in neonatal umbilical cord blood,

and in breast milk in African countries, with

significant seasonal variations (30±32). Levels of

aflatoxins detected in some umbilical cord bloods at

birth are among the highest levels ever recorded in

human tissue and fluids.

Aflatoxins have been suggested as an etiological

factor in encephalopathy and fatty degeneration

of viscera, similar to Reye syndrome, which is

common in countries with a hot and humid climate

(33). The clinical picture includes enlarged, pale, fatty

liver and kidneys and severe cerebral oedema.

Aflatoxins have been found in blood during the

acute phase of the disease, and in the liver of affected

children (Table 2). However, use of aspirin or

phenothiazines is also suspected to be involved in

the etiology (41).

.....

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