sine Toxins

8/3/2019 sine Toxins

http://slidepdf.com/reader/full/sine-toxins 1/35

Animal Feed Science and Technology

114 (2004) 205–239

Toxicological evaluation of trichothecenesin animal feed

Gunnar Sundstøl Eriksen, Hans Pettersson∗

Department of Animal Nutrition and Management, Swedish University of Agricultural Sciences,

P.O. Box 7024, Uppsala S-750 07, Sweden

Received 27 November 2002; received in revised form 23 July 2003; accepted 9 August 2003

Abstract

Trichothecenes are mycotoxins commonly found in cereals world-wide. Fusarium fungi are the

main producers of trichothecenes in cereals. Trichothecenes are rapidly excreted from animals and

residues of trichothecenes in animal-derived food products are not considered to pose any threat

to consumers. The toxins are toxic to all tested species, but the sensitivity varies considerably be-

tween toxins and between species. Available feeding studies with the trichothecenes deoxynivalenol(DON), nivalenol (NIV) and T-2 toxin in feed to production animals have been reviewed. There

are not sufficient available data about the effects of trichothecenes in ruminant feed to allow a

scientifically-based risk assessment. The available studies of the metabolism of trichothecenes in

cattle indicate that trichothecenes to a large extent are transformed to the much less toxic de-epoxide

metabolite in the rumen before absorption. Furthermore, no effect has been found on milk produc-

tion, feed intake or other parameters measured at levels used in the studies. It is concluded that

trichothecenes are not likely to cause any harm in ruminants unless fed visibly damaged feed and

no guideline value is probably needed.

Poultry are more sensitive to trichothecenes than ruminants. Levels from 9 mg DON/kg feed have

lead to negative effects of chickens, while no effect was found in chicken fed 5 mg DON/kg feed,

and a guideline value of 2.5 mg DON/kg feed is proposed. The available information about NIV

does not allow a guideline limit to be set, but the finding of minor pathological changes in chicken

fed 1 mg NIV/kg feed indicates that NIV may be more toxic to poultry than DON. Oral lesions are

observed in chickens and hens fed 1 mg T-2 toxin/kg feed. Other effects, including a reduction in

feed intake, are found with increasing levels of T-2 toxin. A guideline limit of 0.5 mg T-2 toxin/kg is

proposed. Pigs are more sensitive to trichothecenes than other farm animals. The effects occurring

at the lowest levels of trichothecenes are reduced feed intake and weight gain, normally occurring

at levels from 0.6 mg DON/kg feed in naturally contaminated feed. Pigs fed 0.5 mg T-2 toxin/kg

feed reduced their feed intake. Impairment of the immune system has also been observed in pigs at

∗ Corresponding author. Tel.: +46-18-67-21-03.

E-mail address: [email protected] (H. Pettersson).

0377-8401/$ – see front matter © 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.anifeedsci.2003.08.008



206 G.S. Eriksen, H. Pettersson / Animal Feed Science and Technology 114 (2004) 205–239

this level of T-2 toxin in the feed. Guidelines of 0.3 mg DON/kg feed and 0.2 mg T-2 toxin/kg feed

is proposed in pig feed.

© 2004 Elsevier B.V. All rights reserved.

Keywords: Trichothecenes; Cattle; Pig; Sheep; Poultry; Feed

1. Introduction

Trichothecenes are a group of mycotoxins mainly produced by fungi of the Fusarium

genus. The toxins are commonly found world-wide on cereals such as wheat, barley, oats

and maize. Trichothecenes are closely-related sesquiterpenoids (ring structure) with a 12,13

epoxy ring and a variable number of hydroxyl, acetoxy or other substituents. Cereals are

commonly used in feed, and farm animals may therefore consume relatively high amountsof trichothecenes. The trichothecenes causing most concern are T-2 toxin, which is the most

acute toxic trichothecene, HT-2 toxin, nivalenol (NIV) and the most frequently occurring

trichothecene, deoxynivalenol (DON).

Several risk assessments for trichothecenes in human food have been published by dif-

ferent international organisations such as the Nordic Council of Ministers (Eriksen and

Alexander, 1998), the European Union (SCF, 1999, 2000, 2001, 2002) and the WHO/FAO

Joint Expert Committee on Food Additives and Contaminants (JECFA) (JECFA, 2001). EU

is preparing the introduction of maximum limits for trichothecenes in food based on the

risk assessments made by the Scientific Committee for Food (SCF). No recent similar as-

sessment of effects of trichothecenes in animal feed is available. The need for guidelines fortrichothecene concentration even in animal feed is currently being discussed within the Eu-

ropean Union (EU). The main effects of the most common trichothecenes on selected farm

animals are reviewed, the need for guideline values for trichothecenes in feed is discussed

and some guideline values are proposed.

Trichothecenes are rapidly excreted from the animals and the carry-over of the toxins from

animals to humans via animal-derived food products is considered to be of little importance

(Beasley and Lambert, 1990; Eriksen and Alexander, 1998). This aspect is therefore only

briefly discussed in the current review.

2. Biochemical mode of action

Trichothecenes are well-known inhibitors of the protein synthesis. The toxins bind to

the peptidyl transferase, which is an integral part of the 60S ribosomal subunit (review in

Feinberg and McLaughlin, 1989). Trichothecenes also cause apoptosis both in vitro and in

vivo in various organs (Pae et al., 2003; Poapolathep et al., 2002).

Trichothecenes are also shown to inhibit the synthesis of DNA and RNA (review in WHO,

1990). Inhibition of DNA and RNA synthesis has only been observed in concentrations

similar to or higher than the concentrations required for inhibiting the protein synthesis.

The exact mechanism for the inhibition of DNA and RNA synthesis has not yet been shown,but it may be a secondary effect of the inhibition of the protein synthesis or of the apoptotic

effect of trichothecenes.



G.S. Eriksen, H. Pettersson / Animal Feed Science and Technology 114 (2004) 205–239 207

Trichothecenes also affect cell membranes. T-2 toxin changed the permeability of the

cell membrane of myoblasts at concentrations as low as 4 pg/ml (Bunner and Morris, 1988).

Trichothecenes are also shown to interfere with the metabolism of membrane phospholipids

and to increase liver lipid peroxides in vivo (Rizzo et al., 1994). Substances protectingagainst free radicals, such as ascorbic acid, -tocopherol and selenium, protect against the

induction of free radicals by trichothecenes (review in Eriksen and Alexander, 1998).

In addition, some trichothecenes are shown to alter the serotonin activity in the central

nervous system, which is known to be involved in the regulation of food intake (review

in Rotter et al., 1996). Fioramonti et al. (1993) found that DON inhibits small intestinal

motility in rodents, mediated through intestinal serotonin receptors. It is not known whether

the seritonergic effect on the brain is a result of the effect on the peripheral nervous system.

The effect on both peripheral and central seritonergic systems may be involvedin the reduced

feed intake observed in animals, but details remain to be elucidated.

3. Toxicokinetics

The toxicokinetics of trichothecenes has been subject of various reviews (e.g. Swanson

and Corley, 1989; Yagen and Bialer, 1993; IARC, 1993) and only a brief summary will be

presented here.

3.1. Absorption, distribution and excretion

The kinetics of all trichothecenes has not been investigated fully, but the existing data

shows that the toxins are rapidly absorbed. In pigs, T-2 toxin, DON and NIV can be detected

in blood less than half an hour after oral exposure to the toxins. Trichothecenes are rapidly

excreted without any accumulation in any tissue, and only traces of the toxins are found 24 h

after oral or intravenous (iv) exposure to trichothecenes. In pigs, the main route of excretion

after iv injection is the urine, but after oral exposure a significant proportion is also excreted

in the faeces (Swanson and Corley, 1989; Prelusky et al., 1988). Trichothecenes do not

accumulate in animals due to the rapid excretion and only traces (<50 ng/g) can be found

in animal-derived food products.

3.2. Metabolism

Trichothecenes undergo a variety of different metabolic reactions in animals. The major

reactions are hydrolysis to split off side groups, hydroxylations and de-epoxidation. Acety-

lated toxins are rapidly metabolised to the de-acetylated form of the toxin (e.g. T-2 toxin

to HT-2 toxin, fusarenon-X (Fus X) to NIV, 3-acetyl DON to DON). The deacetylation

reactions are fast and are catalysed by specific esterases (Swanson and Corley, 1989).

A 12,13 de-epoxide metabolite of trichothecenes has been detected after oral exposure to

NIV or DON in rats, mice, cattle and sheep and a de-epoxide metabolite was found after iv

injection of T-2 toxin in pigs. De-epoxidation of trichothecenes has also been reported fromincubations of trichothecenes with the microflora from the intestines of a range of species or

with micro-organisms from the rumen of cows (Swanson and Corley, 1989; Swanson et al.,




1988; Kollarczik et al., 1994). These incubation studies have also showed that the microflora

is able to deacetylate trichothecenes. De-epoxide metabolites of trichothecenes have also

been detected in plasma and urine in sheep and cows,but only in low amounts. This reduction

of the epoxide ring is probably carried out by anaerobic gastrointestinal micro-organisms(review in Swanson and Corley, 1989). Some trichothecenes, such as DAS, T-2 toxin and

HT-2 toxin and metabolites thereof, are extensive glucuronide conjugated, while little or

no such conjugation has been found in monogastric animals given DON or NIV (review in

Swanson and Corley, 1989). The absorption of trichothecenes is rapid also in ruminants, but

only low proportions of the administered toxin are accounted for in studies with cattle and

sheep, even when the de-epoxide metabolite is included. This indicates that other unknown

metabolites may be formed in ruminants.

4. Toxicity of trichothecenes

4.1. DON and mono-acetylated derivatives

DON and either of the two mono-acetylated derivatives 3- and 15-acetyl DON are often

found together in cereals. One of the acetylated derivatives normally occurs together with

DON in cereals but the proportion between DON and the acetylated form varies. Acetylated

toxins are rapidly deacetylated in vivo. DON is therefore discussed together with the acety-

lated forms. A provisional maximum tolerable intake (PMTDI) of 1g/kg body weight

(BW) was set by JECFA (2001) and SCF (1999).

4.1.1. Pigs

4.1.1.1. Toxic effects. Many feeding studies of the effects of DON on pigs have been pub-

lished (Table 1). In most cases naturally or artificially infected cereals have been mixed into

the feed. Other compounds produced by the same fungus, either other known mycotoxins

or some other unknown compound may interact with the toxin in these studies. When feed

at a farm is contaminated with DON, it is a result of a natural contamination, and studies

with naturally contaminated feed are therefore included in the text, even if the results may

be influenced by the presence of other substances.

General toxicity Previously DON was also called vomitoxin, referring to the emetic

effect of DON observed in early field reports (Vesonder et al., 1973) and in experiments

where high doses of the toxin were given to the pigs by oral exposure or iv injection.

Complete feed refusal was observed at levels of 12 and vomiting at 20 mg DON/kg feed

(Young et al., 1983; Forsyth et al., 1977). The mechanism for these effects has not been

clarified but changes in the seritonergic activity of both the peripherous and central nervous

system may be involved (Rotter et al., 1996).

Feeding trials where naturally or artificially infected material has been mixed into the diet

have shown decreased feed consumption and weight gain in pigs at doses from 0.6 to 2 mgDON/kg feed (Friend et al., 1982; Overnes et al., 1997; Bergsjo et al., 1993b; Young et al.,

1983). The observed reduction in feed intake at the lowest doses was temporary, but the loss



Table 1

Summary of effects of exposing pigs to DON in feed (n = number of animals in each group)

Breed n Conc. (mg/kg feed) Toxin source Exposure time Effects

Yorkshire (6 weeks) 6 0–9 Pure 7 days Reduced feed intake and weight gainYorkshire (6 weeks) 7

0–3 ad lib and

pair-fed controls

Contaminated maize 28 days Linearly decreased skin temp and thyroid w

feed intake, BW (trend significant, but no di

between groups), corrugated stomach, impro

efficiency, increased serum T4, albumin and

serum-globulin compared to ad lib contro

to pair-fed. reduced antibody response to SR

and 2 weeks, but not after 3. The response d

Landrace× Pietrain (no

age or BW)

9 0.3–1.2 Pure 8 weeks No effect on weight gain, tendency towards

IGF-1 and IgA

Yorkshire (7–8 weeks old) 8

0, 4.0 ad lib and

pair-fed controls

Contaminated maize 42 days Reduced feed intake (20%) and BW gain (1

corrugated stomach compared to controls, te

decreased serum protein after 2 and 3 weeks

temporary reduced-globulin weeks 2–4

Landrace (ca. 25 kg BW) 8 0.1–4.5 Contaminated oat 8 weeks Transient reduced feed consumption and we

Decreased weight gain whole period decreas

utilisation

Landrace (ca. 21 kg) 17–20 0.05–3.50 Contaminated oat Ca. 3 months

(21–100 kg BW)

Transient reduction in PCV

Decreased feed consumption

Decreased serum calcium and phosphorus (<

Increased rel. liver weight

Yorkshire (4–5 weeks) 4 0, 3.4–19.1 Pure or contaminated

wheat

2 weeks Reduced feed intake, reduced BW (partially

if <12 ppm), decreased total serum protein a

phosphorus, reduced alkaline phosphatase

Increased rel. stomach and adr enal weights

Decreased rel. kidney wt.

Reduced feed intake and BW. Increased rel.

weight4–5 0–8.7 Contaminated wheat 7 weeks Increased rel. stomach wt.

Landrace (12–13 weeks) 6 0, 2.5 Contaminated maize 5 weeks Reduced feed intake and weight gain, signifi

changes in stomach mucosa

Yorkshire (12–15 weeks) 5 0, 6 Pure toxin 21 days Reduced feed intake, weight gain and slight

feed efficiency. Lesions in stomach

Yorkshire (9–10 weeks) 3 0–5.2 Contaminated maize

and pure DON

7 weeks Reduced feed intake and BW, increased rel.

and urinary bladder wt., stomach lesions



Table 1 (Continued )


? (16–18 kg BW) 15–16 0–5.26 Contaminated wheat 90–110 days (ca.

17–90kg BW)

Reduced feed intake and increased age at

No significant increase in wt. of kidney, l

uterus. No effect on feed efficiency. Stom

Yorkshire (ca. 25 kg) 12 3.7, 4.2 Contaminated wheat

or maize

7 weeks Decreased feed consumption and wt.

? (7–9 kg) 3–4 0.14–875 Contaminated maize 4–21 days (4 trials) Vomiting

Reduced feed intake and BW

Increased serum protein, albumin, choles

decreased serum P, glucose, alkaline pho

? (crossbred 5 week) 8–10 0.7–5.8 Contaminated maize 4 weeks Reduced feed intake and BW (male more

Reversed in females when given control f

Reddening of mucosa in stomach and sm

and oedema in the mesenteric lymph nod

? (8–9 kg) 10 10.5 ad lib and

pair-fed controls

Contaminated maize 21 days Reduced feed consumption and BW, redu

efficiency (P < 0.07) compared to ad lib

no difference to pair-fed control. Decreas

hematocrit, haemoglobin, glucose, P com

lib control, but higher haemoglobin and nsignificant change compared to pair-fed c

? (ca. 9 kg) 8 0–2.8 Contaminated wheat 2 or 3 weeks Reduced feed intake and BW (no differen

when fed a clean diet after 4 weeks expos

? (ca. 61 kg) 4 0–4.2 Contaminated wheat 42 days Reduced feed intake and BW gain. No ef

weight

? (45 kg) 4 0, 6.3 Contaminated maize

and pure

4 days Reduced feed intake

7.2 Reduced feed intake

? (20 kg) 4 0–40 Pure 4 days Dose-dependent reduction in feed intake

? (20 kg) 3 0–16 Pure 3 days Reduced feed intake, reduced weight gain

? (20 kg) 3.6, 12.5 Contaminated maize 3 days Reduced feed intake, reduced weight gain

receiving 3.6 mg DON/kg naturally conta

had a lower feed intake and average daily

than all pigs receiving pure toxin)

? (ca. 24 kg) 6 or 12 <0.05–11.0 Contaminated wheat 14 weeks Reduced feed intake, vomiting

Reduced weight gain:feed ratio

Landrace (ca. 25 kg) 8 0.6–4.7 Contaminated oat About 100 days

(25–100 kg)

Reduced feed intake, feed conversion and

antibody response toward tetanus toxoid

other antigens, and only after 9 weeks, no

6). Increased lymphocyte response towar

mitogen

Interstitial hepatitis in liver (ca. P = 0.05



Landrace (from 22 k g) 15 0.03, 6.0 Contaminated wheat 12 weeks Reduced feed consumption and weight gain (no

enhanced diet)

? (80–90 kg) 11 8 Contaminated wheat 11 days Reduced feed consumption compared to previou

days. Slowly increasing from day 6

Degeneration of hepatocytes, degenerative chan

renal tubular epithelium and eosinophilic infiltralymphatic organs

Yorkshire (ca. 39 k g) 6 0.05, 0.75 Contaminated wheat 21 days Reduced feed intake and weight gain first 3 day

difference later, but the loss was never recovered

Yorkshire (ca. 75 k g) 6 0.05–0.75 Contaminated wheat 21 days Dose-dependent reduction in feed intake and we

gain first 3 days, which were not recovered.

Discoloration of oesophageal region of the stom

> 0.05)

Yorkshire (ca. 43 k g) 4 (0.05–0.75) Contaminated wheat 7 weeks Reduced feed intake and reduced feed:gain ratio

Yorkshire (ca. 21 k g) 4 (0.05–0.75) Contaminated wheat 4 weeks Reduced wt. gain, significant trend for wt. gain

feed intake

Yorkshire (age and size

not specified)

6 0–0.7 Contaminated wheat 21 days Reduced feed intake and average wt. gain espec

days 1–3

Yorkshire (ca. 30 kg) 10 0.20, 5.08 Contaminated wheat 5 weeks Reduced feed intake and wt. gain

Yorkshire (9 weeks) 6 0–3.0 Contaminated maize

and pure toxin

32 days Reduced feed intake and wt. gain (whole period

nature contaminated, only 2 days for pure toxin)

Significant decrease in serum gammaglobulin co

and trend towards a decrease in total globulin co

No significant pathological changes in stomach

but trend towards more mucosal folding and thic

of oesophageal region tissue with increasing DO

? (60 kg) 6 (2 control) 0, 1.0 Pure 90 days No effect on feed intake or BW or BW gain or o

parameters measured

? (age and size not

specified)

? 0–5 ? Reduced feed intake

Changed feed:wt. gain ratio

? (70–83 days old) 6 0–1.4 Contaminated wheat 100–125 days No effect on feed intake, wt. gain, or other param

measured

? (ca. 30 k g) 12–18 0.2–2.8 Contaminated wheat (30–100 k g BW) No effect on feed consumption, wt. gain or othe

parameters measured

Yorkshire (ca. 90 kg) 12 0.1–3.5 Contaminated wheat 50–54 days (from

178 days, during

pregnancy)

Reduced maternal BW and feed intake

Significant trend towards reduced foetal wts. and

lengths

a NOAEL: no observed adverse effect level; LOAEL: lowest observed adverse effect level.




in weight gain during the first period was not completely compensated for during the later

periods and the animals reach slaughter weight at a higher age. There are two reports of a

reduced feed intake even in pigs fed 0.35 mg/DON/kg feed (Friend et al., 1982; Trenholm

et al., 1983), but the number of animals in each group was quite low (6) and the find-ings have not been reproduced in later studies. In other available studies, a no effect level

cannot be established since effects in feed intake were observed in the lowest levels used

(Table 1).

Changes in different clinical chemistry parameters (plasma nutrients and plasma enzyme

activities) have been reported from several studies (Bergsjo et al., 1993b; Young et al.,

1983; Cote et al., 1985; Chavez, 1984; Lusky et al., 1998). These effects are probably at

least partly due to the reduced feed intake and not a direct effect of the toxin since no

changes in these parameters were observed when compared to pair-fed controls (Lun et al.,

1985).

The consumption of DON-contaminated feed has been associated with epithelial lesions

in the oesophageal region of the stomach when pigs have been given naturally infected

feed containing from about 3 to 6 mg DON/kg feed (Cote et al., 1985; Foster et al., 1986;

Friend et al., 1986c; Rotter et al., 1992, 1995). Changes in kidney tubular epithelium were

observed in one of six pigs in the group given 1.0 mg DON/kg feed for 90 days while

no such changes were found in the two control pigs (Lusky et al., 1998). The authors

concluded that 1.0 mg pure DON/kg feed represented a toxic concentration in the feed.

The present reviewers consider both the incidence of epithelial changes in the animals and

the number of animals in each group to be too low to draw any conclusions and do not

consider 1.0 mg DON/kg feed as a toxic level for pigs based on the study of Lusky et al.(1998).

The effects of pure DON added to feed and naturally contaminated feed containing similar

levels of DON have been compared in at least four feeding studies with pigs. Naturally

infected feed had a stronger effect on the feed intake and weight gain than pure toxin in all

these studies comparing the difference sources of DON (Forsyth et al., 1977; Foster et al.,

1986; Rotter et al., 1994; Trenholm et al., 1994). The difference remains to be explained,

but proposed hypotheses include the presence of other toxins in the material, the presence

of other non-toxic compounds affecting the toxicity of trichothecenes and inducing taste

aversion (Rotter et al., 1996). The results indicate that some factor apart from the toxin

concentration influence the toxicity of feed containing infected material. However, it shouldbe noted that the number of animals used in these studies was low and the variation within

a group was large, at least in some of the studies.

The effect on feed intake occur at a low level of DON in pig feed and is considered to

be the effect occurring at the lowest level of DON. Commonly, no effect has been found

at levels from 0.6 to 1 mg DON/kg feed, but in two studies a temporary reduction on feed

intake was observed even in pigs given 0.35 mg DON/kg feed.

Effects on reproduction. A few studies of the effects of DON on pig reproduction

have been published. Trends towards a lower foetal weights and lengths were reported from

sows fed 1.7 or 3.5 mg DON/kg feed during the pregnancy when the foetuses were examined50–54 days after fertilisation (Friend et al., 1983). No effect of DON on litter size, weights

or size at birth, weight gain during lactation or survival rate have been found. No deformities




or other damages were found in the piglets at the applied doses (0.1–4 mg DON/kg feed)

in the reported experiments (Chavez, 1984; Friend et al., 1986a,b). Considering the results

from these studies, it is considered unlikely that DON would influence reproduction at levels

not having effects on the maternal pigs.

Effects on the immune system. No studies on the effect of DON on infections in pigs

are available. However, a few studies of the immune response towards vaccinations have

been carried out. Rotter et al. (1994) found a delayed immune response towards sheep red

blood cells (SRBC), 1 and 2 weeks after immunisation in pigs given 3 mg DON/kg feed.

The response was significantly reduced compared to a pair-fed control group, but not from a

control group fed ad lib. A significant dose-related reduction in antibody response towards

tetanus toxoid was observed 9 weeks after the start of the experiment in pigs fed 1.8 or

4.7 mg DON/kg feed in the diet compared to control pigs. No effect was found on the four

other antigens tested, including SRBC, or in response towards any antigen after 6 weeks of

exposure (Overnes et al., 1997).

A decreasing trend in serum -globulin was found with increasing DON-levels in pigs

given 0–3 mg DON/kg feed (Rotter et al., 1994). A decreased plasma-globulin concentra-

tion was found in growing pigs fed 4.0 mg DON/kg feed after 2 and 3 weeks, but not after

6 weeks (Rotter et al., 1995). Similarly, a reduction in -globulins was found in pigs fed

3 mg DON/kg feed for 18 days, but not in pigs given 1 mg DON/kg feed (Prelusky et al.,

1994). In contrast to these findings, no effect on total globulin levels or IgA concentra-

tion in plasma was found in other studies with growing pigs given 0–4.9 mg DON/kg feed

(Bergsjo et al., 1992; Götz-Schröm et al., 1998; Lusky et al., 1998). The different resultsmay be due to the natural variation between individual pigs, since the number of animals

in each study was normally rather low compared to the variation (six to eight animals in

each treatment). The different results may also be a result of different breeds, sex, age,

etc. of the pigs used in the studies. The presence of other substances in the feed based on

naturally infected material may also have contributed to the variation between different

experiments, especially since pure toxin was used in some experiments and naturally in-

fected material in others. A dose-response relationship or a clear level that does not have

any effect on the immune system cannot be established based on the available data, but so

far no effect on the immune system has been reported from pigs given 1 mg or less DON/kg

feed.

4.1.1.2. Summary. Interpretation of the results from feeding trials with infected material

is complicated since the presence of other toxic substances in the feed cannot be ruled out. In

most of the studies the contaminated feed had been analysed for other known mycotoxins,

but the number of other toxins looked for and the detection limits for these toxins varies.

In some studies traces of other toxins have been found together with DON. It has also been

shown earlier that the growth of Fusarium fungi can change the nutrient and amino acid

composition of the feed (Williams et al., 1992a,b). Changes in the feed composition may

therefore contribute to the effects observed in feeding trials with infected cereals. Simi-

larly the presence of other substances, known or unknown, may influence the results instudies using infected material in the feed. Some other parameters that may influence the

results from the feeding studies are age, breed and feed composition. Due to the varying




results in feeding studies with cereals infected with Fusarium, a clear dose-response rela-

tionship cannot be established from the available data. However, a DON contamination of

feed in commercial pig production would be a result of a natural infection of the cereals.

It is therefore reasonable to take studies with infected material into consideration whenpreparing a maximum limit for DON in feed. Temporary effects on the feed intake, and

thereby the weight gain, seem to occur at levels from 0.9 mg DON/kg feed and upward

when naturally infected material is used. The effects on feed intake and weight gain are

temporary at the lowest levels, but the reduced weight gain is not compensated for later

on and the exposed pigs reach slaughter weight at a higher age than pigs given uncon-

taminated feed. The influence on the dietary intake of factors other than DON should be

clarified to establish a dose-response curve for DON contamination in pig feed. Effects

on the immune system are found at concentrations exceeding 1.8 mg DON/kg feed, and

complete feed refusal at levels exceeding 12 mg/kg. Whether a low level of DON in the

feed and the reduced feed intake is an animal welfare problem is not known. Based on the

reduction in feed intake it is therefore reasonable to assume no effect of DON in naturally

contaminated feed of about 0.6–1 mg DON/kg feed. The human evaluations are based on

a no observed adverse effect level (NOAEL) of 1g/kg BW in a feeding study with mice,

using a safety factor of 100 (JECFA, 2001; SCF, 1999). To compare the toxicity between

species, the dose is expressed relative to the body weight. Furthermore, a safety factor of

10 is included in the factor 100 used for extrapolation between species. A low safety fac-

tor is justified in this evaluation since the data come from the actual species, the effects

at the lowest levels are transient and no long-term toxicity, e.g. cancer, is expected to be

of any concern since the life-time for the pigs is relatively short. The reviewers thereforeconsider a safety factor of 2 to be sufficient. All data are derived from studies with pig

feed, which the proposed guideline value is intended for. Guideline value expressed as a

concentration in feed, which is more directly applicable, is proposed and a maximum limit

of DON of 0.3 mg DON/kg feed for pigs, despite the fact that clear dose-response relation-

ship remains to be established. Basing the maximum limit on the lowest observed effect

level in any study would probably protect the pigs from serious effects of DON, but the

proposed maximum limit may be lower than necessary for certain pigs or certain types of

feed.

4.1.2. Cattle

4.1.2.1. Toxic effects. Only a few feeding studies with dairy cows are available. Cows have

been given a concentrate containing 6.4 mg DON/kg feed for 6–10 weeks (Trenholm et al.,

1985) or feed containing 8.5 mg DON/kg for 3 weeks (Ingalls, 1996). A slight temporary

decrease in consumption of the concentrate was recorded when the concentrate concentra-

tion of DON was increased from 1.5 to 6.4 mg/kg concentrate in the first study. No effect

was seen on weight gain, or hay consumption. The concentrate consumption returned to the

previous levels when the cows after 6–10 weeks again were fed the concentrate containing

1.5 mg DON/kg. In the second study, no significant effect was found on feed intake, weight

gain, milk yield, milk composition and rumen pH. A non-significant tendency towards a re-duced feed intake in the third week was observed, but according to the authors this decrease

was not related to levels of DON. No sign of illness was observed in the studies ( Trenholm




et al., 1985; Ingalls, 1996). The latter study gives no information about either analytical

methods or uncertainties, making it difficult to assess the information from the study.

The inclusion of 5.0 or 12.1 mg DON/kg dry matter in a feed concentrate for 10 weeks

had no effect on the volume of milk produced or intake of forage. Neither DON nor itsde-epoxide metabolite were detected in the milk when it was analysed with a method

having a detection limit of 1 ng/ml (Charmley et al., 1993).

Samples of milk have been analysed for DON after exposing cows to either a single dose

of 920 mg DON/animal (Prelusky et al., 1984) or a dietary concentration of 66 mg DON/kg

feed for 5 days (Cote et al., 1986). DON was not found in the milk in any of the studies,

but a much less toxic de-epoxide metabolite was found for 5 days when one single cow was

given approximately 300 mg DON per day in the feed for 5 days (Cote et al., 1986).

Effects on reproduction. No data available.

Effects on the immune system. No data available.

4.1.2.2. Summary. Cattle seem to be quite tolerant towards DON. No effect of DON on

cows has been found when the animals were given feed containing up to 12 mg/kg feed.

Furthermore DON is metabolised to the much less toxic de-epoxide metabolite by the

rumen microflora. Trichothecenes are not accumulated in meat and excretion in milk has

only been reported after exposure to very high levels of the toxin. Trichothecenes do not

therefore reduce the quality of cattle-derived food products. The reviewers do not regard

the levels of DON that may be expected to occur in feed as a risk, either for animal healthor foods produced from cattle, and a maximum level for DON in cattle feed is not needed.

4.1.3. Sheep

4.1.3.1. Toxic effects. Even if various studies of the kinetics of DON in sheep have been

reported, very few feeding trials studying toxic effects of DON on sheep are available.

Harvey et al. (1986) fed lambs with a wheat diet containing 15.6 mg DON/kg feed for 28

days. Feed consumption, weight gain, and feed efficiency of the lambs given DON did not

differ from the control animals. No differences between treated and untreated lambs were

noted for haematological or serum biochemical variables, and no gross or microscopiclesions were observed in treated lambs. In another study, intrarumen dosing with 5 mg

DON/kg BW to sheep resulted in a 44% decline in feed intake and a decrease of 5% in

apparent digestibility of the feed (Brewer et al., 1996). The dose used in the experiment was

very high and it is very unlikely that sheep will get such a high exposure to trichothecenes

under natural conditions.

4.1.3.2. Summary. There are not enough studies on the effects of DON with sheep to

allow an evaluation. However, studies of trichothecene metabolism in sheep suggest that

trichothecenes are de-epoxidased and extensively glucuronidated in sheep, which are there-

fore likely to be rather resistant towards these toxins. It is unlikely that the levels of tri-chothecenes in feed for sheep will be of any practical importance and there is probably no

need for any guideline value for trichothecenes in feed for sheep.




4.1.4. Poultry

4.1.4.1. Toxic effects.

General toxicity. Many studies of the effects on DON on hens and chickens, espe-

cially chickens, have been published (Table 2). Chickens have low sensitivity towards DON

compared to pigs, and feed refusal and reduced weight gain are only found when the con-

centration reaches 16–20 mg DON/kg feed (Kubena et al., 1987a, 1988, 1989b; Kubena

and Harvey, 1988; Harvey et al., 1991). Only one high dose level was used in these studies,

and consequently no observed adverse effect level or lowest observed adverse effect level

(LOAEL) could be established. Kubena et al. (1985) found a decreased relative and absolute

liver weight and increased relative and absolute gizzard weight in chickens fed 9 or 18 mg

DON/kg feed for days 1–35 of age, but no other changes in growth, feed intake or relative

organ weights were observed in the chickens. A LOAEL of 9 mg DON/kg feed could be set

from the study.

Effects on reproduction DON up to 83 mg/kg feed did not have any effect on the egg

production rate in laying hens. The hatchability was not affected by levels of up to 18 mg

DON/kg feed (Hamilton et al., 1985a; Kubena et al., 1987b; Bergsjo et al., 1993a; Lun et al.,

1986). A low increase in the incidence of minor malformations that could be considered

as delayed foetal maturation (delayed ossification, unwithdrawn yolk sac) were observed

in chick embryos from hens given a feed containing 2.5 or 3.1 mg DON/kg, but not in the

group given 4.9 mg DON/kg feed (Bergsjo et al., 1993a). No such increase in malformationswas found in another experiment when hens were given 0–4.9 mg DON/kg feed (Hamilton

et al., 1985a). Based on these studies it is concluded that it is unlikely that DON have any

significant effect on the reproduction at these low levels of DON in the feed.

Effects on the immune system. No studies on the effect of DON on the resistance towards

infections have been reported. Harvey et al. (1991) conducted a series of experiments

investigating the effects of DON on the different parameters of the immune system of

growing chickens. The researchers found a reduced response towards vaccination against

Newcastle disease in female Leghorn chickens given a diet based on naturally infected

wheat containing 18 mg DON/kg feed for 18 weeks. No effect was found in broilers giventhe same diet for 9 weeks. Blastogenic response of spleenocytes was significantly reduced

in female Leghorn chickens given a diet containing 18 mg DON/kg feed from naturally

infected wheat. No such effect was seen in the males given the same diet nor in male or

female Leghorn chickens given a diet containing 50 mg pure DON/kg feed. The blastogenic

response was significantly reduced in female, but not in male broiler chickens given 50 mg

pure DON/kg feed. It was concluded that Leghorn chicks are less sensitive than broiler

chicks (Hubbard × Hubbard), that male chickens are less sensitive than females and that

pure toxin is less toxic than naturally contaminated wheat.

Other effects. The effects of DON on the monoamine neurotransmitters in the brainof poultry were studied in two experiments. Significant changes in biogenic monoamine

metabolism were observed in some brain regions of hens given a single dose of 2.5 mg







White Leghorn (23–26

weeks)

12 0.12–4.9 Contaminated oat 70 days Small increase in incidence of anomalies in chick off

two middle concentrations, but not the highest)

White Leghorn (335-day-old) 24 0, 18 Contaminated wheat 112 days Small s ignificant decreased egg shell wt. and shell pe

and increased albumin height

White Leghorn 24 20 Pure 6 days Radioactive labelled DON found in the eggs with a m

concentration the last day of exposure of 0.07mg/kg wdecline when switched to clean feed

Hubbard× Hubbard (day 1) 60 0, 16 Contaminated wheat 3 weeks Reduced growth, increased feed efficiency, increased

weight, anaemia, decreased LDH, and serum triglyce

White Leghorn × single

comb. (26 weeks)

10 0, 83 Contaminated wheat 27 days Small er osions in the gizzard, no other pathological c

White Leghorn (192 days) 102 <0.5–0.7 Contaminated wheat 70 days Decreased egg weight, shell weight, shell thickness (

not given)

White Leghorn 28, 56 0.2–4.9 Contaminated wheat 24 weeks No significant effects

Di ff erent types 3 0–0.70 Contaminated wheat 86 or 135 days Incr eased liver triglycer ides and total liver lipid in 0.3





DON/kg BW by gavage. The studies showed a different pattern of changes in the brain

monoamine metabolism between rats and hens (Fitzpatrick et al., 1988). The dose used in

the experiment was high and poultry is unlikely to reach such a dose by consumption of

contaminated feed.

Effects on the quality of the food products. Studies with 5.5 mg radioactive labelled

DON/kg feed to six laying hens for 65 days showed that the radioactivity in the eggs

increased to a maximum level corresponding to 1.7g DON or metabolites/egg at the

eighth day of exposure. The levels levelled out and decreased thereafter. The radioactivity

in the eggs decreased to about 25% of the maximum after 30 days, and remained relatively

constant for the rest of the exposure period. The radioactivity in the eggs quickly dropped to

negligible values when the exposure to DON ceased. The authors concluded that although

DON can be transferred to the eggs, the levels are low and do not pose any hazard to human

health (Prelusky et al., 1989). The intake of a maximum of 1.7g/egg is of little significance

compared to the estimated intake of 0.5–2.5g/kg BW from cereals (JECFA, 2001).

4.1.4.2. Summary. Chickens are not as sensitive to DON as pigs. The available data indi-

cate that levels of 5 mg/kg feed do not cause any damage to the birds, while altered organ

weights were found in chickens given 9 mg DON/kg feed. There are some conflicting results

from studies of the effect of 5 mg DON/kg feed on the development of chicken foetuses.

Indeed a low, but significant, increase of minor malformations was reported in one study,

but not in the other. With a safety factor of 2, a level of 2.5 mg DON/kg feed can be regarded

as safe for DON in chicken feed.

4.2. Fusarenon-X and nivalenol

Fus X is only distinguished from NIV by an acetyl group at the C-4 position. Moreover,

Fus X is rapidly deacetylated to NIV. Both toxins are therefore included in this assessment.

Few studies have been performed with NIV or Fus X on farm animals. All studies available

to the authors will be discussed in the chapters treating the different species. Nivalenol was

evaluated by SCF who set at TDI of 0.7g NIV/kg BW, using a large safety factor of 1000

due to the limited database.

4.2.1. Pigs


General toxicity. No sign of altered feed intake or body weight and no vomiting or

clinical problem were observed in young male pigs (pathogen-free Swedish Landrace ×

Yorkshire) given 2.5 or 5 mg purified NIV/kg feed in the diet for 3 weeks (Hedman et al.,

1997). A reduction in feed intake was found in pigs given a diet containing 5.8 mg NIV/kg

feed or more, but not in pigs given a diet containing 2.9 mg NIV/kg feed (Williams et al.,

1994; Williams and Blaney, 1994). The feed in these last feeding trials also contained zear-alenone, and estrogenic effects were observed in the pigs. An interaction with zearalenone

or other compounds present in the infected maize cannot be excluded.




Macroscopic examinations of pigs fed NIV revealed mild and foecal haemorrhagic dam-

ages or changes in the thickness of the mucosa in the gastrointestinal tract in two out of six

and five out of six pigs fed 2.5 or 5 mg NIV/kg feed, respectively (Hedman et al., 1997).

Altered kidney appearance was observed in animals from both exposed groups (4/6 pigsand 5/6 pigs fed 2.5 and 5 mg NIV/kg feed, respectively). In 2/6 and 1/6 pig fed 2.5 or

5 mg NIV/kg feed, respectively, cysts of approximately 1 cm in diameter were found in

the kidneys. No change in weights of liver, heart, spleen, or thymus was observed in the

exposed groups compared to the control (Hedman et al., 1997).

Effects on reproduction. No data available.

Effects on the immune system. No information about effects of NIV on resistance

towards infections is available. A dose-dependent reduction in spleen cell number was

found in young male pigs given 2.5 or 5 mg NIV/kg feed for 3 weeks of exposure compared

to the control animals, but only the highest dose group was significantly different from

the control group. The number of both CD4+ and CD8+ were reduced, but the proportion

between the two types was not changed. Plasma IgA was not statistical different from control

pigs at any time (Hedman et al., 1997).

4.2.1.2. Summary. Few feeding studies with NIV on pigs have been performed and the

database is not sufficient to provide a scientific base for any guidelines for NIV in pig feed.

A comparison of the existing data from feeding trials with similar data for DON indicates

that the toxic effects of NIV occurs at about the same levels as for DON. We thereforepropose that until more information eventually becomes available, a temporary limit could

be set at the same level as for DON, i.e. 0.3 mg/kg feed.

4.2.2. Cattle

No data available.

4.2.3. Sheep

No data available.

4.2.4. Poultry


General toxicity. A statistically significant dose-related decrease in feed consump-

tion and weight gain was observed in chickens fed 6 and 12 mg NIV/kg feed, while birds

fed 3 mg/kg feed were not significantly different from the controls (Hedman et al., 1995;

Pettersson et al., 1995). There was no difference between the feed intake or growth of

laying hens receiving 3 or 5 mg NIV/kg feed for 50 days compared to a control group

(Garalevieciene et al., 2002).

Relative liver weight was reduced in chickens given 12 mg NIV/kg feed, while no effectwas found in chickens given 6 mg NIV/kg feed (Hedman et al., 1995; Pettersson et al., 1995)

or in laying hens given 5 mg NIV/kg feed (Garalevieciene et al., 2002). Increased incidence




of gizzard erosions were found in chickens fed 3–12 mg NIV/kg feed (Hedman et al., 1995;

Pettersson et al., 1995) and in laying hens fed 3 or 5 mg NIV/kg feed butnot in hens fed 1 mg

NIV/kg feed (Garalevieciene et al., 2002). The uric acid concentration in plasma increased

by 94 and 66% in chicks fed 2.5 or 5 mg NIV/kg feed from days 7 to 27 of age comparedto the control group. No such increase in plasma uric acid was observed in chickens fed

0–12 mg NIV/kg feed from days 7 to 27 of age (Hedman et al., 1995; Pettersson et al., 1995).

A slight haemorrhage was found in the initial part of the duodenum in laying hens given

1, 3 or 5 mg NIV/kg feed (1/5, 3/5 and 2/4 hens at the levels of 1, 3 and 5 mg NIV/kg feed,

respectively). In addition, swelled cloaca and oviducts (2/5 and 3/4) were found in hens

fed the 3 or 5 mg NIV/kg feed, respectively. The swollen oviducts and abdominal cavity of

these hens were filled with a liquid containing fibrin conglomerates, immature egg yolks

and eggs in different stages of development. Some of the eggs were found in the cloaca

cavity. No such observation was reported from the control birds. No change in organ weights

was reported from this experiment (Garalevieciene et al., 2002). In addition, the alkaline

phosphatase activity was slightly decreased in birds given 5 mg NIV/kg diet. Some non

dose-dependent pathological changes were also found in the kidneys.

Effects on reproduction. Egg production or egg quality was not affected in laying hens

given 1–5 mg NIV/kg feed for 50 days (Garalevieciene et al., 2002).

Effects on the immune system. No data available.

Other effects. The bursa of Fabricus degenerated during development and necrosis of

the epithelial cells in the lymphoid follicles was observed after injection of high doses of Fus

X or NIV (5 mg/kg BW) to 1-day-old chicks (Terao et al., 1978). The study demonstrates

a potential effect of the toxins on the development of the birds, but the dose was very high

compared to realistic exposure levels from the feed.

4.2.4.2. Summary. The available information on the toxicity of NIV to poultry is sparse

and is not sufficient to provide any scientific base for a maximum value for NIV in poultry

feed. Some minor pathological changes were found in hens fed 1 mg NIV/kg feed. This

indicates that NIV may be more toxic to chickens than DON, but the available information

is not sufficient to draw any conclusions. The data available does not permit any guidelinelimit to be proposed.

4.3. T-2 toxin and HT-2 toxin

T-2 toxin is the most acute toxic trichothecene produced by Fusarium fungi. T-2 toxin is

only distinguished from HT-2 toxin by an acetyl group in the C-4 position. Usually HT-2

toxin occurs together with T-2 toxin in the infected cereal. HT-2 toxin is also a major

metabolite of T-2 toxin, which is rapidly formed after exposing an animal to T-2 toxin. It is

therefore difficult to distinguish the effects of T-2 toxin and HT-2 toxin in vivo. The authors

therefore find it reasonable to deal with these together in a risk assessment of the toxins.There is no feeding study with HT-2 study available, and the assessment will therefore be

based on feeding trials with T-2 toxin only. JECFA evaluated T-2 and HT-2 toxins and




proposed a PMTDI of 60 ng/kg BW for the sum of the two toxins, using a safety factor

of 500, because there were no clear NOAEL in the study the limit is based upon, and

deficiencies in the database (JECFA, 2001).

4.3.1. Pigs


General toxicity. Feeding trials with T-2 toxin in pig feed are summarised in Table 3.

Most feeding trials with T-2 toxin in pigs have been performed over a short period and

quite high doses have been used in many of the trials. Reduced feed intake or complete feed

refusal and reduced weight gain are commonly observed when pigs are fed T-2 toxin. Only

high doses have been used in many studies of the effects of T-2 toxin on feed intake and body

weight gain. Reduced feed intake and weight gain have been found in pigs given 5–10 mg

T-2 toxin/kg feed in these studies (Harvey et al., 1990, 1994; Rafai et al., 1989; Rafai and

Tuboly, 1982). It has not been possible to determine a NOEL in these studies since some

effects were normally found even at the lowest dose used in the trials. The reduction in feed

intake is often accompanied by changes in different haematological and clinical parameters.

These changes are likely, at least partly, to be a consequence of the reduced feed intake.

Rafai et al. (1995a) observed a reduction in feed intake in 7 weeks old pigs fed as little

as 0.5 mg or more purified T-2 toxin/kg feed for 3 weeks. The reduction in feed intake was

accompanied by a significant reduction in weight gain and plasma glucose and by increased

concentrations of magnesium and inorganic phosphorus in plasma in pigs given 1.0 mg T-2toxin/kg feed or more. Similarly, a statistically significant decreased feed intake was found

in pigs given 0.4–3.2 mg pure T-2 toxin/kg feed while the decrease in body weight gain was

insignificant. Statistical comparisons between dose groups were not done in the study and a

NOAEL cannot be determined (Friend et al., 1992). Complete feed refusal was observed in

pigs given a feed containing 16 mg T-2 toxin/kg, but not 10–12 mg/kg (Weaver et al., 1978a).

Histological changes were found in the subepithelial layers of the lips, snout and in the

mouth in pigs given 1.0 mg T-2 toxin/kg feed and higher. Skin inflammations and changes

in the mucus membrane of the oral cavity and mouth were seen in pigs given 4.0 mg T-2

toxin/kg feed. No significant change in feed conversion rate was observed (Rafai et al.,

1995a). No histopathological changes were detected in pigs given 0.4–3.2 mg T-2 toxin/kgfeed (Friend et al., 1992) or in piglets given 1–16 mg T-2/kg feed for 8 weeks (Weaver et al.,

1978a).

Different breeds of pig, different ages of the pigs and different sources of the toxin with

different purity have been used in the studies and may explain some of the variation in the

reported studies.

Effects on reproduction Different parameters of reproductive effects of T-2 toxin in

pigs have been studied. Abortion was induced by iv injection of 0.2–0.4 mg T-2 toxin/kg

BW (Weaver et al., 1978b). The levels are high and the study is not considered to be relevant

for an exposure from levels likely to occur in feed not visibly infected by mould.Increased mortality of piglets was observed when two sows were given a culture material

of F. sporotrichioides mixed into the feed, giving a concentration of 8.3 mg T-2 toxin/kg



Table 3

Summary of effects of exposing pigs to T-2 toxin in feed (n = number of animals in each group)

Breed n Conc.

(mg/kg feed)

Toxin source Exposure time Effects

Landrace 2 (1 control) 8 Culture Last quarter of

gestation and 3

weeks after birth

Increased mortality of piglets after birth, reduced plas

piglets, pathological changes in liver, stomach, adrena

adrenal cortex, and liver of piglets, reduced no. of lym

spleen, increased infection rate

Landrace× large

white (ca. 9 kg)

10 0–15.0 Pure 3 weeks Reduced feed intake

Reduced weight gain and plasma glucose concentratio

plasma inorganic phosphorus and magnesium concen

histological changes in the subepithelial layers in lips

the mouth

Reduced plasma-free fatty acids (trend)

Weight loss, skin inflammations and changes on the m

of the oral cavity and tongue

Landrace× largewhite (ca. 9 kg)

10 0–3.0 Pure 3 weeks Decreased leukocyte count, T-lymphocyte proportionlymphocytes, reduced titre of antibodies to horse glob

proliferative response to PHG and CON A

Decreased Hgb levels in blood

Landrace× Yorkshire

(12–13 weeks)

6 0–3.2 Pure 5 weeks Non-significant trend towards reduced weight gain, re

intake. No statistics on differences between groups

Yorkshire × Landrace

(7 weeks)

9 0, 8 Pure 30 days Reduced feed consumption and weight gain

Increased ALP, reduced Hgb

No significant effect on other clinical chemistry param

response as measured by blastogenesis and phagocyto

kidney or spleen

Castrates 6 0, 10 Pure 28 days Reduced BW, and wt. gain, decreased blood urea, iron

Hgb, MCV, MCH, number of lymphocytes Increased

triglycerides, increased rel. heart wt.

? ? 0, 13.52 T-2

+ 5.42 HT-2

Extract

(F. sporotrichoides)

? Reduced feed intake and weight gain, uterus and ovar

mucous membrane in uterus, follicle atresia

Large white × duroc 6 0, 5 ? 25 days Feed refusal, reduced weight gain, decreased leukocy

increased adrenocortical function, reduced blastogeni

immune rosette formation, reduced response towards

clostridial haemorrhagic enteritis




Breed n Conc.

(mg/kg feed)

Toxin source Exposure time Effects

Hungarian large white

× duroc

6 0, 5 ad lib Pure 25 days

(from 35 days)

Reduced feed consumption and weight gain, reduced leuko

decreased immune response (measured by antigen-induced

transformation, IgG positive cell counts, response towards

reduced antibody formation in response to immunisation w

necrotic enteritis), reduced relative thymus and spleen weig

Increased plasma cortisol level and rel. adrenals weight

Landrace 2 0.1 mg/kg BW p.o. Pure 14 or 36 days Leucopenia

(Crossbred from 10

days after weaning)

4 0–8 Pure 8 weeks Reduced feed consumption and body weight during first w

2 0–32 Pure 2 days at each

dose level

Reduced feed consumption

Feed refusal

? (adult sows) 1–2 12 Pure 80–220 days Repeat breeders

Reduced litter size and litter weight

No effect in offspring





feed during the last quarter of gestation until 1 week after farrowing (Vanyi et al., 1991). In

contrast to this, the piglet mortality did not increase when two adult sows were given 12 mg

purified T-2 toxin/kg feed during the third trimester of pregnancy and until 6 weeks after

delivery when the piglets were weaned (Weaver et al., 1978c). The dead piglets from thefirst study were necropsied and the findings included degeneration of the liver and kidneys,

enteritis, lymphocyte depletion, necrosis in lymphoid follicles and atrophy of the thymic

cortex. T-2 toxin and the metabolites HT-2 toxin, T-2 triol and neosolaniol were all found in

the sows’ milk. No lesion was found in the piglets from the second study and the only effect

of the toxin reported in that study was reduced litter size. An eventual presence of other

toxins may explain the high toxicity of the culture material used in the first study compared

to pure toxin used in the second study. Cultures of F. sporotrichioides commonly produce

HT-2 toxin, and even other mycotoxins like DAS, neosolaniol and fusarin C, in addition to

T-2 toxin (Eriksen and Alexander, 1998) and some of these toxins may have been present

in the material since the T-2 toxin was not purified. A significant uterus atrophy was found

in pigs when 6-week-old piglets were given an extract of F. sporotrichioides mixed into the

feed for an unspecified exposure period, giving a toxin concentration of 13.52 mg T-2 and

5.42 mg HT-2 toxins/kg feed in the final feed (Palyusik et al., 1990).

All effects reported from these studies of the reproductive effects of T-2 toxin in pigs occur

at high toxin levels not likely to occur in feed not visibly moulded. Other trichothecenes do

not have any effect on the reproduction in doses not having toxic maternal effects. Similarly,

T-2 and HT-2 toxins are not considered to have any reproductive effects in rodents at doses

not having maternal effects (JECFA, 2001). It is therefore concluded that effect on the

reproduction is not likelyto occur at levels not having other toxic effects. Anyguideline valuefor the T-2 and HT-2 toxins in feed should therefore not be set based on reproductive effects.

Effects on the immune system. No data on the effects of T-2 toxin on resistance towards

infections in pigs are available. Decreased antibody response towards injected horse globulin

and decreased plasma leukocyte count were found in 7-week-old pigs given 0.5–3 mg pure

T-2 toxin/kg feed for 3 weeks. A dose-dependent depletion of lymphoid elements in thymus

and spleen was found in the pigs at the end of the experiment. Decreased proliferative

response to mitogen stimulants PHG and CON A were observed in exposed pigs after 21

days of exposure, but not after 7 and 14 days (Rafai et al., 1995b).

Reduced leukocyte count, blastogenic response and reduced response towards antigenswere also observed in other studies with pigs given the higher dose of 5 mg T-2 toxin/kg

feed (Rafai et al., 1989; Rafai and Tuboly, 1982). The latter study also revealed reduced

relative weights of thymus and spleen in the exposed pigs.

4.3.1.2. Summary. Reduced feed intake and impairment of the immune system appear to

be the effects occurring in pigs at the lowest level of T-2 toxin in feed, both effects found in

pigs fed 0.5 mg pure T-2 toxin/kg feed. A large safety of 500 was used in the evaluations of

risk to humans (SCF, 2001; JECFA, 2001) because no NOAEL was found in the study and

due to deficieties in the database. A lower safety factor is justified in the evaluation for pig

feed since the data come from the actual species, the effects at the lowest levels are transientand no long-term toxicity, e.g. cancer, is expected to be of any concern since the life-time

for the pigs is relatively short. Taking into account the fact that no effect was observed at




similar levels in other studies and the fact that the toxicity data are derived from data from

the actual species, a low safety factor is justified. Based on the LOAEL of 0.5 mg/kg feed,

we suggest that the concentration of T-2 toxin in pig feed should not exceed 0.2 mg/kg feed.

4.3.2. Cattle

4.3.2.1. Toxic effects. Few controlled studies of the toxic effects of T-2 toxin on cattle

using oral exposure have been published. Feed refusal, diarrhoea, decreased weight, de-

creased thymus and adrenal weights and decreased plasma IgA and IgM were observed in

calves given 0.6 mg T-2 toxin/kg BW in the feed (about 20 mg/kg feed). This dose of the

toxin even altered the response to mitogens in calves. The calves fed 0.3 mg T-2 toxin/kg

BW (10 mg/kg feed) had a partial feed refusal but weight gain and other measured haema-

tological, immunological or other parameters were not different from controls (Osweiler

et al., 1985).

Several studies of the metabolism of T-2 toxin in cattle have demonstrated a rapid

metabolism of the toxin leading to both conjugated and de-epoxidated compounds, consid-

ered to be much less toxic than T-2 toxin itself (Swanson and Corley, 1989). Low levels

of T-2 toxin and/or metabolites are found in milk after experimental exposure of cows to

high levels of T-2 toxin, but to our knowledge, the toxin has not been found in milk from

cows from commercial milk production. It is not likely that T-2 toxin in milk would pose

any threat to milk consumers.

The toxicological database available is not sufficient to perform any risk assessment of

T-2 toxin in cattle feed. However, the little toxicological data available and the informationon metabolism of the toxin in cattle indicate that cattle are rather resistant towards T-2 toxin

and the levels occurring in feed that is not visibly infected by mould is not likely to be of

any concern for cattle.

4.3.3. Sheep

4.3.3.1. Toxic effects. ThereappeartobenotoxicologicaldataforT-2toxininsheep.How-

ever, metabolic studies have been published. The studies show that trichothecenes are rapidly

metabolised to less toxic conjugates and de-epoxides in sheep and we find it unlikely that

T-2 toxin will reach a level of any concern in feed not severely infected by mould.

4.3.4. Poultry


General toxicity. Chickens: Studies of T-2 toxin in poultry feed have revealed effects

such as reduced feed intake, body weight gain and feed efficiency (summarised in Table 4).

The feed intake and body weight gain were lowered when purified T-2 toxin was mixed into

the feed at levels of 2–6 mg T-2 toxin/kg feed, while no such reduction in feed intake was

observed in chickens given 1 mg T-2 toxin/kg feed. The reduction in feed consumption andbody weight gain in these studies were observed either over the whole exposure period or

during the first 2 weeks of exposure (Raju and Devegowda, 2000; Wyatt et al., 1972, 1973b;



Table 4

Summary of effects of exposing chickens to T-2 toxin in feed (n = number of animals in each group)

Animal n Conc. (mg/kg feed) Toxin source Exposure time Effects

? commercial (day 1) 20 0, 3 Culture

material

35 days Reduced feed intake and BW, decreased plasma urea, decre

a non-significant increase in adrenal weight (from 56 to 103

weight)

Hybro 0, 0.5 Pure 2 weeks Histopathological changes in heart, duodenum, kidney

Broiler (age not specified) No consistent change in enzyme activity

Broiler chicks (from day 1) 40 0–16 Pure 3 weeks Oral lesions

Reduced BW gain

Increased numbers of bacteria in mouth fluids

Broiler (unspecified) (day 1) 0–16 Pure 3 weeks Reduced growth

Increased prothrombin time

Arbor Acress × Vantress (day 1) 12 0–4.0 Pure 9 weeks Increased rel. heart weight

Oral lesions

Reduced weight gain

Broiler (not specified) (day 1) 40 0–16 Pure 3 weeks Dose-related altered feathering

Broiler chicks 40 0, 16 Pure 3 weeks Decreased rel. wt. of bursa of Fabricus, and spleen

(Cobb × Cobb) (day 1) Increased mortality after infection with Salmonella spp.

White Leghorn 10 0–10 one

pair-fed control

Pure 4 weeks Decreased BW, compared to control and pair-fed control, in

rel. wt. of Bursa and spleen

Lesions in the tongue

Reduced serum albumin

Hubbard× Hubbard (day 1) 60 0, 4 Pure 3 weeks Oral lesions, decreased BW, serum protein, albumin, potass

magnesium, activity of LDH, AP

Hubbard× Hubbard (day 1) 60 0, 4 Pure 3 weeks Oral lesions, reduced rel. bursa wt., decreased serum albumiprotein and LDH

Hubbard× Hubbard (day 1) 60 0, 4 Pure 3 weeks Decreased BW gain, serum Hgb, MCV, MCHgbC, Ca, Mg,

protein, albumin, CK, LDH



Broiler (unspecified) (day 1) 40 0–16 Pure 3 weeks Reduced BW

Increased faeces lipids, decreases pancreatic lipase, trypsin

and Rnase

Peterson× Hubbard (day 1) 20 0, 6 Pure 3 weeks Oral lesions, reduced BW, increased rel. gizzard weight, de

bursa weight, decreased MCV and decreased serum protein

and glucose

Indian River (day 1) 40 0–16 Pure 3 weeks Reduced growth rate, altered rel. weights of spleen and pan

Altered rel. weight of bursa of Fabricus and crop

Broiler (unspecified) (day 1) 40 0–16 Pure 3 weeks Neurological disturbances

New Hampshire 10 23–460 Contaminated

grain

8–30 days Reduced feed consumption, reduced BW, oral and oesopha

lesions, haemorrhages in intestines and kidney, swelling of

Fabricus, decreased haemoglobin, number of leukocytes, er

and thrombocytes

New Hampshire 16 8, 16 Pure 8–30 days Oral lesions, decreased haemoglobin, number of leukocyte

erythrocytes and thrombocytes

Dekalb 131 (30 weeks) 10 0, 20 Pure 3 weeks Oral lesions, decreased feed consumption, reduced BW, red

plasma protein, plasma lipids, leukocyte number, reduced e

production and shell thickness

White Leghorn (27 weeks) 24 0–8.0 Pure 8 weeks Oral lesions

Increased LDH

Reduced feed consumption, egg production, shell thicknesshatchability, increased, AP and serum uric acid, decreased s

glutamic–pyruvic transaminase

White Leghorn 6 0–16 Contaminated

corn

28 days Oral lesions

0–16 Pure toxin 21 days Reduced feed intake, wt. gain, egg production

Reduced feed intake and egg production

No significant effect on BW, blood parameters

SSL (28 weeks) 10 0–10 Pure 4 weeks Decreased egg production

White Leghorn (33 weeks) 10 0, 2 Pure 24 days Oral lesions, reduced feed intake, reduced egg production





Doerr et al., 1974; Chi et al., 1977b; Huff et al., 1988; Kubena et al., 1989a, 1994; Osborne

et al., 1982). In contrast to the above-mentioned studies, the reduction in feed intake and

weight gain was observed only during the last week of a 4-week exposure period when

chickens were given 2 or 10 mg T-2 toxin/kg feed (Richard et al., 1978). Even the feedefficiency was reduced in this study, especially during the last week of the trial.

Histopathological changes in heart, liver, duodenum and kidney were reported from ex-

aminations of chickens fed as low a concentration as 0.5 mg pure T-2 toxin/kg feed for 2

weeks. The lesions persisted for 4 weeks after the end of the exposure period (Grabarevic

et al., 1992). No information was given about feed composition, feed intake, possible pres-

ence of other trichothecenes in the feed or the number of animals with histopathological

changes in each group and no explanation was given for the liver changes. The present

reviewers consider the study to be inadequate for evaluation and a guideline value should

not be based on this study.

Oral lesions were observed in chickens given a feed containing 1 mg T-2 toxin/kg feed

or more (Wyatt et al., 1972; Chi et al., 1977b; Huff et al., 1988; Kubena et al., 1989b ).

Increased relative gizzard weight and decreased relative weight of the Bursa of Fabricus

have been found after examinations of chickens exposed to levels exceeding 4–6 mg T-2

toxin/kg feed (Richard et al., 1978; Kubena et al., 1989b, 1994).

Laying hens: In most studies, a reduction in feed intake and/or body weight gain was

observed in hens when exposed to levels from 8 mg T-2 toxin/kg feed, while no change in

feed intake was found in hens given 4–8 mg T-2 toxin/kg feed (Wyatt et al., 1975a; Chi

et al., 1977a; Speers et al., 1977; Tobias et al., 1992). In contrast to this, a statistically

significant reduction in feed intake by 10% was reported from one study where hens weregiven 2 mg T-2 toxin/kg feed for 3 weeks. The decreased feed intake was not accompanied

by any significant reduction in body weight gain (Diaz et al., 1994). T-2 toxin caused oral

lesions in hens fed 0.5 mg T-2 toxin/kg feed (Diaz et al., 1994) or 1.0 mg T-2 toxin/kg feed

(Chi et al., 1977a). In the latter study the frequency of oral lesions between hens fed 0.5 mg

T-2 toxin/kg feed was not significant from the control group.

Effects on reproduction. Egg production was significantly decreased compared to con-

trol group when hens have been given concentrations of T-2 toxin in the feed from 8 mg T-2

toxin/kg feed (Wyatt et al., 1975a; Chi et al., 1977a; Speers et al., 1977; Tobias et al., 1992).

In one study the egg production was significantly lower in hens fed 2 mg T-2 toxin/kg feedwhen calculated over the whole exposure period, but the difference between the exposed

and control hens was not significant at any specific sampling period (Diaz et al., 1994). The

results indicate that egg production may be reduced at a lower level than 8 mg T-2 toxin/kg

feed, but such a the difference may be hard to detect due to either a large variation in egg

production or a low number of animals at each sampling time.

Effects on the immune system. The mortality was significantly increased in male broiler

chickens given 16 mg pure T-2 toxin/kg feed inoculated with Salmonella worthington, S.

thompson, S. derby, and S. typhimurium var. copenhagen compared to the control chickens

(Boonchuvit et al., 1975). Decreased resistance towards bacteria was also found when anincreased number of bacteria were found in the mouth fluids in chickens fed 4, 8 or 16 mg

pure T-2/kg in the diet for 3 weeks from hatching. No effect was found in chickens given




a diet containing 2 mg T-2 toxin/kg feed (Wyatt et al., 1972). The formation of antibodies

in chickens immunised towards Pasteurella multocida was not significantly changed in

chickens exposed to 2 or 10 mg T-2 toxin/kg feed. No change in the white blood cell count

was found in chickens given 10 mg T-2 toxin/kg feed compared to the controls, but serumalbumin was reduced (Richard et al., 1978).

The studies indicate that the immune system of the chickens may be reduced when the

concentration of T-2 toxin reaches 4 mg T-2 toxin/kg feed or higher.

Other effects. Neurological disturbances, measured as abnormal wing positioning, loss

of righting reflex, and hysteroid seizures, and altered feathering were observed in chickens

fed 4 mg T-2 toxin/kg feed or more, while no effect was observed in chickens at doses of

2 mg/kg or lower (Wyatt et al., 1973a, 1975b). The biological significance of these findings

remains uncertain.

4.3.4.2. Summary. The effect of T-2 toxin occurring at the lowest levels of feed contam-

ination reported is oral lesions, which are observed in chickens and hens given 1.0 mg T-2

toxin/kg feed, while reduction in feed intake and weight gain are observed at levels from

2 mg/kg feed. Using a safety factor of 2 would give a maximum concentration of 0.5 mg

T-2 toxin/kg feed.

5. Interactions with Fusarium toxins

The difference in toxicity between naturally contaminated cereals and pure toxin added

to non-contaminated grain in the same concentrations has not been explained. Proposed ex-

planations include interference with other mycotoxins not detected in the grain and interfer-

ence from substances not toxic per se, but which may enhance the toxicity of trichothecenes.

Some studies also indicate that the nutritional value of cereals changes when infected by

Fusarium fungi.

5.1. Combined effects of trichothecenes

The effects of combined exposure to trichothecenes have been performed, both in vitroand in vivo.

The effects of the combined exposure to T-2 toxin, HT-2 toxin and a macrocyclic tri-

chothecene, on the growth of the yeast Kluyveromyces marxianus has been found to vary

from antagonistic to synergistic, depending on test conditions and which trichothecenes

used (Koshinsky and Khachatourians, 1992; Madhyastha et al., 1994). The mechanism of

the yeast growth inhibition is unknown and the relevance to animal toxicity is therefore

uncertain.

Additive effects of most combinations of trichothecenes have been reported both from

studies measuring protein inhibition in Vero cells (monkey kidney cells) (Thompson and

Wannemacher, 1986) and from studies when combinations of DON, 15-aDON and HT-2toxin were tested in a chick embryotoxicity bioassay (Rotter et al., 1991). In contrast to these

findings, an antagonistic effect of DON was found on the proliferation of human peripheral




lymphocytes stimulated with phytohaemagglutinin or pokeweed when combined with T-2

toxin or DAS. Nivalenol in combinations with DAS, DON or T-2 toxin had additive effects

in the same assay (Thuvander et al., 1999).

A few in vivo studies of the combined effects of trichothecenes have also been published.No effect of 2 mg 3- or 15-acetyl DON was found when pigs were given feed with or

without 6 mg DON/kg. DON reduced the feed intake and weight gain, but no effect of

acetyl-DON was observed (Rotter et al., 1992). Only the lowest and highest doses (0.4 and

3.2 mg T-2 toxin/kg feed, respectively) of T-2 toxin interfered with the effects of 2.5 mg

DON/kg feed in a 5 week feeding study. The intermediate doses of T-2 toxin (0.8 or 1.6)

did not alter the effect of DON on these parameters (Friend et al., 1992).

The combined effects of T-2 toxin and DAS was found to be additive in an acute toxicity

test with hens (Hoerr et al., 1981). Additive effect was also found on feed intake and oral

lesions when laying hens were given 2 mg T-2 toxin, 2 mg DAS or the combination of the two

toxins in a 24 days feeding study (Diaz et al., 1994). Feed containing 16 mg DON/kg feed

slightly, but not significantly, increased the incidence and severity of oral lesions observed

in hens given 4 mg T-2 toxin/kg feed. No other significant effects of the combination of the

two toxins were found (Kubena et al., 1989b).

The Scientific Committee for Food in the European Union recently evaluated the tri-

chothecenes T-2 toxin, HT-2 toxin, nivalenol and deoxynivalenol as a group (SCF, 2002).

Based on the limited toxicological database, the differences in toxicity observed in vivo,

large non-systematic potency differences between the toxins when different toxic effects

are considered and the few studies of the combined effects in vivo, the committee concluded

that the risk assessment for trichothecenes as a group in human food could not be done.SCF therefore decided that a group tolerance level for the trichothecenes could not be set

and a TDI should be set for each of the evaluated trichothecenes (allowing a group TDI for

T-2 toxin and HT-2 toxin).

The database for evaluating any combined effects of trichothecenes on farm animals is

not sufficient at present.

5.2. Combined effects of trichothecenes and other Fusarium toxins

Even the effects of combined exposure to trichothecenes and other mycotoxins produced

by Fusarium fungi have been studied, both in vitro and in vivo.The effect of DON, zearalenone and the combination of the two toxins on induction of

human and rat lymphocyte proliferation was studied. Both toxins caused a dose-dependent

reduction in proliferation, but the concentration of zearalenone required to inhibit the pro-

liferation by 50% was 250 times higher than for DON. The combined exposure of the toxins

had additive effects (Atkinson and Miller, 1984).

A feeding study has been performed of the combined effects of zearalenone and DON in

pigs. Varying amounts of purified zearalenone (0–6 mg ZEN/kg feed) were added to natu-

rally contaminated wheat containing 0–5 mg DON/kg feed. Dietary ZEN did not affect feed

intake, weight gain or feed conversion. However, there was a statistically significant linear

decrease in feed consumption and weight gain with increasing levels of DON. Analysis of variance did not show any significant interaction between the two toxins (P = 0.35), but an

indication of a greater reduction in feed intake when ZEN was present in any concentration




was found (P = 0.08). Dietary DON increased the relative weights of the stomach, uterus

and adrenals. ZEN did not affect the relative weight of these organs, but increased the organ

weight of the uterus. The estrogenic effect of ZEN, measured as days to appearance of a

swollen vulva, was weakened by DON at low levels of ZEN. At higher levels of ZEN, DONdid not affect the estrogenic effects of ZEN (Trenholm et al., 1988). ZEN did not affect

DON-toxicity measured by the same parameters in mice (Forsell et al., 1986).

The effects of exposing pigs to combinations of 0.1 mg ochratoxin A, 1.0 mg DON and

0.25 mg zearalenone/kg feed were investigated in a 90 days feeding study (Lusky et al.,

2001). None of the toxins nor any combinations of them had any significant effect on body

weight gain over the period.

Rotter et al. (1992) exposed growing pigs for 2 or 3 weeks to feed containing the Fusarium

graminearum metabolites sambucinol, culmorin and dihydroxycalcitonin, in addition to 15-

and 3-acetyl DON discussed above, and with or without 6 mg DON/kg feed. The only signif-

icant effects seen were reduced feed consumption and weight gain when DON was present in

the feed. No significant combined effects between DON and the other toxins were observed.

A non-significant difference was found between sambucinol and culmorin with and without

DON, but the number of animals in each group was very low (n = 2) (Rotter et al., 1992).

The effects of combined exposure of pigs to DON and fusaric acid was studied in three

different feeding trials (Smith et al., 1997). DON in the feed decreased the feed intake and

weight gain. When the level of DON was constant, the feed intake and weight gain were

decreased by increasing levels of fusaric acid. Similarly, when the levels of fusaric acid

were constant, the feed intake and weight gain decreased when the DON-concentration in

the feed was increased. The authors report a decreased feed consumption in pigs fed as low aconcentration of DON as 0.5 mg/kg feed, but significant amounts of fusaric acid were found

in the diet and this may have influenced the toxicity. Acute toxic doses of fusaric acid to

pigs lead to vomiting and changes in the seritonergic system (Smith and MacDonald, 1991).

These effects are also observed in pigs given DON, but the mechanism for the changes in the

seritonergic system is different. Changes in the brain seritonergic system are also observed

after intake of other anorectic substances (Rotter et al., 1996). It is therefore possible that

fusaric acid may affect the effects of DON on feed intake, but the available information is

not sufficient to clarify this. Fusaric acid is not often looked for in cereals and the importance

of the substance in food or feed remains unknown.

Fusarium fungi are also shown to produce other toxins, like beuvaricin and monili-formin. These toxins, like sambucinol, culmorin and dihydroxycalcitonin discussed above,

are not often analysed for in cereals, and therefore little information about the occurrence

is available. No information about how these compounds may influence the toxicity of

trichothecenes is available.

6. Conclusions

6.1. Pigs

Pigs are more sensitive to trichothecenes than other farm animals. The effects occurring

at the lowest levels of trichothecenes in pig feed are reduced feed intake and weight gain.




Feed refusal is observed in pigs given 0.5 mg T-2 toxin or 0.6 mg DON/kg feed, but higher

levels did not lead to any effects in some studies. The few available feeding studies with

simultaneous exposure to two or more trichothecenes indicates that no synergistic effects are

observed. We therefore suggest that the lowest proposed limit of 0.2 mg T-2 toxin/kg feedshould apply to the sum of trichothecenes if T-2 toxin or HT-2 toxin is present. Otherwise

the guideline of 0.3 mg DON/kg feed should be applied for the sum of trichothecenes present

in the feed. The guidelines, especially for DON should be regarded as temporary, since so

far no clear dose-response relationship has been found on the feed refusal in pigs by DON.

Factors affecting the effects of DON need to be systematically tested to establish such a

dose-response relationship.

6.2. Ruminants

Little information about the toxicity of trichothecenes in ruminants is available. Metabolic

studies have shown that trichothecenes to a large extent are detoxified in the rumen. The

few available studies also indicate that ruminants are rather resistant towards trichothecenes

compared to pigs. There is not enough information available to make a scientific evaluation

of the risk associated with trichothecenes in feed for ruminants, but the available information

indicates that levels normally found in feed do not constitute a risk for ruminants. There is

therefore probably no need for guidelines for trichothecene levels in feed for ruminants.

6.3. Poultry

Chickens are not as sensitive to trichothecenes as pigs, but probably more sensitive than

ruminants. The available data indicate that levels of 5 mg DON/kg feed does not cause any

damage to the birds and a level of 2.5 mg DON/kg feed may be regarded as a safe level for

DON in chicken feed. Some studies indicate that NIV may be more toxic to poultry than

DON, but there are not enough data available to set any safe level for NIV in poultry feed.

Oral lesions are observed in chickens given 1.0 mg T-2 toxin/kg feed. A safety factor of 2

would give a maximum concentration of 0.5 mg T-2 toxin/kg feed. The authors therefore

suggest that the sum of trichothecenes in feed should not exceed 0.5 mg/kg feed if several

toxins are present, while a guideline limit of 2.5 mg DON/kg feed should be applied if only

DON and the acetylated derivatives are present in the feed.

References

Atkinson, H.A., Miller, K., 1984. Inhibitory effect of deoxynivalenol, 3-acetyldeoxynivalenol and zearalenone on

induction of rat and human lymphocyte proliferation. Toxicol. Lett. 23, 215–221.

Beasley, V.R., Lambert, R.J., 1990. The apparently minimal hazard posed to human consumers of products from

animals fed trichothecene-contaminated grains. Vet. Hum. Toxicol. 32 (Suppl.), 27–39.

Bergsjö, B., Kaldhusdal, M., 1994. No association found between the ascites syndrome in broilers and feeding of

oats contaminated with deoxynivalenol up to thirty-five days of age. Poult. Sci. 73, 1758–1762.

Bergsjo, B., Matre, T., Nafstad, I., 1992. Effects of diets with graded levels of deoxynivalenol on performance ingrowing pigs. J. Vet. Med. A 39, 752–758.

Bergsjo, B., Herstad, O., Nafstad, I., 1993a. Effects of feeding deoxynivalenol-contaminated oats on reproduction

performance in White Leghorn hens. Br. Poult. Sci. 34, 147–159.




Bergsjo, B., Langseth, W., Nafstad, I., Jansen, J.H., Larsen, H.J., 1993b. The effects of naturally

deoxynivalenol-contaminated oats on the clinical condition, blood parameters, performance and carcass

composition of growing pigs. Vet. Res. Commun. 17, 283–294.

Boonchuvit, B., Hamilton, P.B., Burmeister, H.R., 1975. Interaction of T-2 toxin with Salmonella infections of chickens. Poult. Sci. 54, 1693–1696.

Brewer, D., Mcalees, A.J., Taylor, A., 1996. Ovine ill-thrift in Nova Scotia. 13. Anorexia and digestibility decline

in female lambs given 3,7,11-3H3-3-acetoxy-7,15-dihydroxy-12,3-epoxytrichothec-9-en-8-one. Proc. Nova

Scotia Inst. Sci. 41, 39–47.

Bunner, D.L., Morris, E.R., 1988. Alteration of multiple cell membrane functions in L-6 myoblasts by T-2 toxin:

an important mechanism of action. Toxicol. Appl. Pharmacol. 92, 113–121.

Charmley, E., Trenholm, H.L., Thompson, B.K., Vudathala, D., Nicholson, J.W.G., Prelusky, D.B., Charmley,

L.L., 1993. Influence of Level of deoxynivalenol in the diet of dairy cows on feed intake, milk production, and

its composition. J. Dairy Sci. 76, 3580–3587.

Chavez, E.R., 1984. Vomitoxin-contaminated wheat in pig diets: regnant and lactating gilts and weaners. Can. J.

Anim. Sci. 64, 717–723.

Chavez, E.R., Rheaume, J.A., 1986. The significance of the reduced feed consumption observed in growing pigsfed vomitoxin-contaminated diets. Can. J. Anim. Sci. 66, 277–287.

Chi, M.S., Mirocha, C.J., Kurtz, H.F., Weaver, G., Bates, F., Shimoda, W., 1977a. Effects of T-2 toxin on

reproductive performance and health of laying hens. Poult. Sci. 56, 628–637.

Chi, M.S., Mirocha, C.J., Kurtz, H.J., Weaver, G., Bates, F., Shimoda, W., 1977b. Subacute toxicity of T-2 toxin

in broiler chicks. Poult. Sci. 56, 306–313.

Cote, L.M., Beasley, V.R., Bratich, P.M., Swanson, S.P., Shivaprasad, H.L., Buck, W.B., 1985. Sex-related reduced

weight gains in growing swine fed diets containing deoxynivalenol. J. Anim. Sci. 61, 942–950.

Cote, L.M., Dahlem, A.M., Yoshizawa, T., Swanson, S.P., Buck, W.B., 1986. Excretion of deoxynivalenol and its

metabolite in milk, urine, and feces of lactating dairy cows. J. Dairy Sci. 69, 2416–2423.

Diaz, G.J., Squires, E.J., Julian, R.J., Boermans, H.J., 1994. Individual and combined effects of T-2 toxin and

DAS in laying hens. Br. Poult. Sci. 35, 393–405.Doerr, J.A., Huff, W.E., Tung, H.T., Wyatt, R.D., Hamilton, P.B., 1974. A survey of T-2 toxin, ochratoxin, and

aflatoxin for their effects on the coagulation of blood in young broiler chickens. Poult. Sci. 53, 1728–1734.

Eriksen, G.S., Alexander, J. (Eds.), 1998. Fusarium Toxins in Cereals—A Risk Assessment. Nordic Council of

Ministers, Copenhagen.

Farnworth, E.R., Hamilton, R.M., Thompson, B.K., Trenholm, H.L., 1983. Liver lipid levels in White Leghorn

hens fed diets that contained wheat contaminated by deoxynivalenol (vomitoxin). Poult. Sci. 62, 832–836.

Feinberg, B., McLaughlin, C.S., 1989. Biochemical mechanism of action of trichothecene mycotoxins. In: Beasley,

V.R. (Ed.), Trichothecene Mycotoxicosis Pathophysiologic Effects, vol. I. CRC Press, Boca Raton, pp. 27–35.

Fioramonti, J., Dupuy, C., Dupuy, J., Bueno, L., 1993. The mycotoxin, deoxynivalenol, delays gastric emptying

through serotonin-3 receptors in rodents. J. Pharmacol. Exp. Ther. 266, 1255–1260.

Fitzpatrick, D.W., Boyd, K.E., Wilson, L.M., Wilson, J.R., 1988. Effect of the trichothecene deoxynivalenol on

brain biogenic monoamines concentrations in rats and chickens. J. Environ. Sci. Health B 23, 159–170.Forsell, J.H., Witt, M.F., Tai, J.H., Jensen, R., Pestka, J.J., 1986. Effects of 8-week exposure of the B6C3F1 mouse

to dietary deoxynivalenol (vomitoxin) and zearalenone. Food Chem. Toxicol. 24, 213–239.

Forsyth, D.M., Yoshizawa, T., Morooka, N., Tuite, J., 1977. Emetic and refusal activity of deoxynivalenol to swine.

Appl. Environ. Microbiol. 34, 547–552.

Foster, B.C., Trenholm, H.L., Friend, D.W., Thompson, B.K., Hartin, K.E., 1986. Evaluation of different sources

of deoxynivalenol (vomitoxin) fed to swine. Can. J. Anim. Sci. 66, 1149–1154.

Friend, D.W., Trenholm, H.L., Elliot, J.I., Thompson, B.K., Hartin, K.E., 1982. Effect of feeding

vomitoxin-contaminated wheat to pigs. Can. J. Anim. Sci. 62, 1211–1222.

Friend, D.W., Trenholm, H.L., Fiser, P.S., Thompson, B.K., Hartin, K.E., 1983. Effect on dam performance and

fetal development of deoxynivalenol (vomitoxin) contaminated wheat in the diet of pregnant gilts (physiological

or toxicological effect). Can. J. Anim. Sci. 63, 689–698.Friend, D.W., Trenholm, H.L., Young, J.C., Thompson, B.K., Hartin, K.E., 1984. Effect of adding potential

vomitoxin (deoxynivalenol) detoxicants or a F. graminearum inoculated corn supplement to wheat diets fed to

pigs. Can. J. Anim. Sci. 64, 733–741.




Friend, D.W., Thompson, B.K., Trenholm, H.L., Hartin, K.E., Prelusky, D.B., 1986a. Effects of feeding

deoxynivalenol (DON)-contaminated wheat diets to pregnant and lactating gilts and on their progeny. Can.

J. Anim. Sci. 66, 229–236.

Friend, D.W., Trenholm, H.L., Thompson, B.K., Fiser, P.S., Hartin, K.E., 1986b. Effect of feeding diets containingdeoxynivalenol (vomitoxin)-contaminated wheat or corn on the feed consumption, weight gain, organ weight

and sexual development of male and female pigs. Can. J. Anim. Sci. 66, 765–775.

Friend, D.W., Trenholm, H.L., Thompson, B.K., Prelusky, D.B., Hartin, K.E., 1986c. Effect of deoxynivalenol

(DON)-contaminated diet fed to growing-finishing pigs on their performance at market weight, nitrogen

retention and DON excretion. Can. J. Anim. Sci. 66, 1075–1085.

Friend, D.W., Thompson, B.K., Trenholm, H.L., Boermans, H.J., Hartin, K.E., Panich, P.L., 1992. Toxicity of T-2

toxin and its interaction with deoxynivalenol when fed to young pigs. Can. J. Anim. Sci. 72, 703–711.

Garalevieciene, D., Pettersson, H., Elwinger, W., 2002. Effects on health and blood plasma parameters of laying

hens by pure nivalenol in the diet. J. Anim. Physiol. Anim. Nutr. 86, 389–398.

Götz-Schröm, S., Schollenberger, M., Lauber, U., Muller, H.-M., Drochner, W., 1998. Wirkung von reinem

Deoxynivalenol bei Läuferschweinen-Ergebnisse. In: Wolff, J., Betsche, T. (Eds.), Procedinggs of the 20th

Workshop on Mycotoxins, pp. 171–175.Grabarevic, Z., Nemanic, A., Jagic, V., Tisljar, M., Artukovic, B., Dzaja, P., Culjak, K., Rinck, I., 1992. Subacute

toxicity of T-2 toxin and DAS in broiler chicks. Vet. Arch. 62, 317–324.

Hamilton, R.M., Thompson, B.K., Trenholm, H.L., Fiser, P.S., Greenhalgh, R., 1985a. Effects of feeding White

Leghorn hens diets that contain deoxynivalenol (vomitoxin)-contaminated wheat. Poult. Sci. 64, 1840–1852.

Hamilton, R.M., Trenholm, H.L., Thompson, B.K., Greenhalgh, R., 1985b. The tolerance of White Leghorn and

broiler chicks, and turkey poults to diets that contained deoxynivalenol (vomitoxin)-contaminated wheat. Poult.

Sci. 64, 273–286.

Harvey, R.B., Kubena, L.F., Corrier, D.E., Witzel, D.A., Phillips, T.D., Heidelbaugh, N.D., 1986. Effects of

deoxynivalenol in a wheat ration fed to growing lambs. Am. J. Vet. Res. 47, 1630–1632.

Harvey, R.B., Kubena, L.F., Huff, W.E., Corrier, D.E., Rottinghaus, G.E., Phillips, T.D., 1990. Effects of treatment

of growing swine with aflatoxin and T-2 toxin. Am. J. Vet. Res. 51, 1688–1693.

Harvey, R.B., Kubena, L.F., Huff, W.E., Elissalde, M.H., Phillips, T.D., 1991. Hematologic and immunologictoxicity of deoxynivalenol (DON)-contaminated diets to growing chickens. Bull. Environ. Contam. Toxicol.

46, 410–416.

Harvey, R.B., Kubena, L.F., Elissalde, M.H., Rottinghaus, G.E., Corrier, D.E., 1994. Administration of ochratoxin

A and T-2 toxin to growing swine. Am. J. Vet. Res. 55, 1757–1761.

Harvey, R.B., Kubena, L.F., Rottinghaus, G.E., Turk, J.R., Casper, H.H., Buckley, S.A., 1997. Moniliformin from

Fusarium fujikuroi culture material and deoxynivalenol from naturally contaminated wheat incorporated into

diets of broiler chicks. Avian Dis. 41, 957–963.

Hedman, R., Pettersson, H., Engstrom, B., Elwinger, K., Fossum, O., 1995. Effects of feeding

nivalenol-contaminated diets to male broiler chickens. Poult. Sci. 74, 620–625.

Hedman, R., Thuvander, A., Gadhasson, I., Reverter, M., Pettersson, H., 1997. Influence of dietary nivalenol

exposure on gross pathology and selected immunological parameters in young pigs. Nat. Toxins 5, 238–246.

Hoerr, F.J., Carlton, W.W., Yagen, B., 1981. The toxicity of T-2 toxin and diacetoxyscirpenol in combination for

broiler chickens. Food Cosmet. Toxicol. 19, 185–188.

Huff, W.E., Kubena, L.F., Harvey, R.B., Hagler, W.M., Swanson, S.P., Phillips, T.D., Creger, C.R., 1986. Individual

and combined effects of aflatoxin and deoxynivalenol (DON, vomitoxin) in broiler chickens. Poult. Sci. 65,

1291–1298.

Huff, W.E., Harvey, R.B., Kubena, L.F., Rottinghaus, G.E., 1988. Toxic synergism between aflatoxin and T-2

toxin in broiler chickens. Poult. Sci. 67, 1418–1423.

Hulan, H.W., Proudfoot, F.G., 1982. Effects of feeding vomitoxin contaminated wheat on the performance of

broiler chickens. Poult. Sci. 61, 1653–1659.

IARC, 1993. Toxins derived from Fusarium graminearum, F. culmorum and F. crookwellense: zearalenone,

deoxynivalenol, nivalenol and fusarenone X. IARC Monogr. Eval. Carcinog. Risks Hum. 56, 397–444.

Ingalls, J.R., 1996. Influence of deoxynivalenol on feed consumption by dairy cows. Anim. Feed Sci. Technol. 60,297–300.

JECFA, 2001. Deoxynivalenol. Joint FAO/WHO Expert Commitee on Food Additives, 56th report. Safety

evaluation of certain mycotoxins in food. WHO Food Additives Series 47. WHO, Geneva, pp. 419–556.




Joffe, A.Z., Yagen, B., 1978. Intoxication produced by toxic fungi Fusarium poae and F. sporotrichioides in chicks.

Toxicon 16, 263–273.

Kollarczik, B., Gareis, M., Hanelt, M., 1994. In vitro transformation of the Fusarium mycotoxins deoxynivalenol

and zearalenone by the normal gut microflora of pigs. Nat. Toxins 2, 105–110.Koshinsky, H.A., Khachatourians, G.G., 1992. Trichothecene synergism, additivity, and antagonism: the

significance of the maximally quiescent ratio. Nat. Toxins 1, 38–47.

Kubena, L.F., Harvey, R.B., 1988. Response of growing Leghorn chicks to deoxynivalenol-contaminated wheat.

Poult. Sci. 67, 1778–1780.

Kubena, L.F., Swanson, S.P., Harvey, R.B., Fletcher, O.J., Rowe, L.D., Phillips, T.D., 1985. Effects of feeding

deoxynivalenol (vomitoxin)-contaminated wheat to growing chicks. Poult. Sci. 64, 1649–1655.

Kubena, L.F., Harvey, R.B., Corrier, D.E., Huff, W.E., Phillips, T.D., 1987a. Effects of feeding deoxynivalenol

(DON,vomitoxin)-contaminated wheatto femaleWhite Leghorn chickens fromday old through egg production.

Poult. Sci. 66, 1612–1618.

Kubena, L.F., Harvey, R.B., Phillips, T.D., Holman, G.M., Creger, C.R., 1987b. Effects of feeding mature White

Leghorn hens diets that contain deoxynivalenol (vomitoxin). Poult. Sci. 66, 55–58.

Kubena, L.F., Huff, W.E., Harvey, R.B., Corrier, D.E., Phillips, T.D., Creger, C.R., 1988. Influence of ochratoxinA and deoxynivalenol on growing broiler chicks. Poult. Sci. 67, 253–260.

Kubena, L.F., Harvey, R.B., Huff, W.E., Corrier, D.E., Philips, T.D., Rottinghaus, G.E., 1989a. Influence of

ochratoxin A and T-2 toxin singly and in combination on broiler chickens. Poult. Sci. 68, 867–872.

Kubena, L.F., Huff, W.E., Harvey, R.B., Phiips, D., Rottinghaus, G.E., 1989b. Individual and combined toxicity

of deoxynivalenol and T-2 toxin in broiler chicks. Poult. Sci. 68, 622–626.

Kubena, L.F., Smith, E.E., Gentles, A., Harvey, R.B., Edrington, T.S., Phillips, T.D., Rottinghaus, G.E., 1994.

Individual and combined toxicity of T-2 toxin and cyclopiazonic acid in broiler chicks. Poult. Sci. 73, 1390–

1397.

Leitgeb, R., Lew, H., Wetscherek, W., Böhm, J., Quinz, A., 1999. Einfluss von Fusarientoxinen auf die Mast und

Schlachtleistung von Broilern. Die Bodenkultur 50, 57–66.

Lun, A.K., Young, L.G., Lumsden, J.H., 1985. The effects of vomitoxin and feed intake on the performance andblood characteristics of young pigs. J. Anim. Sci. 61, 1178–1185.

Lun, A.K., Young, L.G., Moran, E.T., Hunter, D.B., Rodriguez, J.P., 1986. Effects of feeding hens a high level of

vomitoxin-contaminated corn on performance and tissue residues. Poult. Sci. 65, 1095–1099.

Lusky, K.V., Göbel, R., Tesch, D., Tenner, G., Haider, W., Krueger, M., Lippert, A., 1998. Studies on the effects

of ochratoxin A and deoxynivalenol toxicity on the health of pigs and tissue residue concentrations. Tierarztl.

Umsch. 53, 623–630.

Lusky, K.V., Göbel, R., Tesch, D., Doberschutz, K.D., Lusky, K., Haider, W., 2001. The effects of mycotoxins

OTA, ZEA and DON on the health and residue values of pigs. Tierarztl. Umsch. 56, 15–20.

Madhyastha, M.S., Marquardt, R.R., Abramson, D., 1994. Structure–activity relationships and interactions among

trichothecene mycotoxins as assessed by yeast bioassay. Toxicon 32, 1147–1152.

Marpegan, M.R., Perfumo, C.J., Godoy, H.M., Sala de Miguel, M., Diaz, E., Risso, M.A., 1988. Feed refusal of

pigs caused by fusarium mycotoxins in Argentina. J. Vet. Med. Ser. A 35, 610–616.Moran, E.T., Hunter, B., Ferket, P., Young, L.G., McGirr, L.G., 1982. High tolerance of broilers to vomitoxin from

corn infected with Fusarium graminearum. Poult. Sci. 61, 1828–1831.

Osborne, D.J., Huff, W.E., Hamilton, P.B., Burmeister, H.R., 1982. Comparison of ochratoxin, aflatoxin and T-2

toxin for their effects on selected parameters related to digestion and evidence for specific metabolism of

carotenoids in chickens. Poult. Sci. 61, 1646–1652.

Osweiler, G.D., Hook, B.S., Buening, G.M., 1985. Aspects of Fusarium mycotoxicosis in livestock. In: Lacey, J.

(Ed.), Trichothecenes and other Mycotoxins. Wiley, New York, pp. 447–462.

Overnes, G., Matre, T., Sivertsen, T., Larsen, H.J.S., Langseth, W., Reitan, L.J., Jansen, J.H., 1997. Effects of diets

with graded levels of naturally deoxynivalenol-contaminated oats on immune response in growing pigs. J. Vet.

Med. Ser. A 44, 539–550.

Pae, H.O., Oh, G.S., Choi, B.M., Seo, E.A., Oh, H., Shin, M.K., Kim, T.H., Kwon, T.O., Chung, H.T., 2003.Induction of apoptosis by 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diolfrom Isaria japonica Yasudathrough

intracellular reactive oxygen species formation and caspase-3 activation in human leukemia HL-60 cells.

Toxicol. In Vitro 17 (1), 49–57.




Palyusik, M., Harrach, B., Horvath, G., Mirocha, C.J., 1990. Experimental fusariotoxicosis of swine produced by

zearalenone and T-2 toxins. J. Environ. Pathol. Toxicol. Oncol. 10, 52–55.

Patterson, D.S., Matthews, J.G., Shreeve, B.J., Roberts, B.A., McDonald, S.M., Hayes, A.W., 1979. The failure

of trichothecene mycotoxins and whole cultures of Fusarium tricinctum to cause experimental haemorrhagicsyndromes in calves and pigs. Vet. Rec. 105, 252–255.

Pettersson, H., Hedman, R., Engstrom, B., Elwinger, K., Fossum, O., 1995. Nivalenol in Swedish cereals—

occurrence, production and toxicity towards chickens. Food Addit. Contam. 12, 373–376.

Poapolathep, A., Ohtsuka, R., Kiatipattanasakul,W., Ishigami, N., Nakayama, H., Doi, K., 2002. Nivalenol-induced

apoptosis in thymus, spleen and Peyer’s patches of mice. Exp. Toxicol. Pathol. 53 (6), 441–446.

Pollmann, D.S., Koch, B.A., Seitz, L.M., Mohr, H.E., Kennedy, G.A., 1985. Deoxynivalenol-contaminated wheat

in swine diets. J. Anim. Sci. 60, 239–247.

Prelusky, D.B., 1997. Effect of intraperitoneal infusion of deoxynivalenol on feed consumption and weight gain

in the pig. Nat. Toxins 5, 121–125.

Prelusky, D.B., Trenholm, H.L., Lawrence, G.A., Scott, P.M., 1984. Nontransmission of deoxynivalenol

(vomitoxin) to milk following oral administration to dairy cows. J. Environ. Sci. Health B 19, 593–609.

Prelusky, D.B., Trenholm, H.L., Hamilton, R.M.G., Miller, J.D., 1987. Transmission of [14C]deoxynivalenol toeggs following oral administration to laying hens. J. Agric. Food Chem. 35, 182–186.

Prelusky, D.B., Hartin, K.E., Trenholm, H.L., Miller, J.D., 1988. Pharmacokinetic fate of 14C-labeled

deoxynivalenol in swine. Fundam. Appl. Toxicol. 10, 276–286.

Prelusky, D.B., Hamilton, R.M., Trenholm, H.L., 1989. Transmission of residues to eggs following long-term

administration of 14C-labelled deoxynivalenol to laying hens. Poult. Sci. 68, 744–748.

Prelusky, D.B., Gerdes, R.G., Underhill, K.L., Rotter, B.A., Jui, P.Y., Trenholm, H.L., 1994. Effects of low-level

dietary deoxynivalenol on haematological and clinical parameters of the pig. Nat. Toxins 2, 97–104.

Rafai, P., Tuboly, S., 1982. Effect of T-2 toxin on adrenocortical function and immune response in growing pigs.

Zentralbl. Veterinarmed. B 29, 558–565.

Rafai, P., Tuboly, S., Tury, E., 1989. Effect of T-2 fusariotoxin on adrenocortical function and some immunological

parameters in growing pigs. Magy. Allatorv. Lapja 44, 299–303.Rafai, P., Bata, A., Vanyi, A., Papp, Z., Brydl, E., Jakab, L., Tuboly, S., Tury, E., 1995a. Effect of various levels

of T-2 toxin on the clinical status, performance and metabolism of growing pigs. Vet. Rec. 136, 485–489.

Rafai, P., Tuboly, S., Bata, A., Tilly, P., Vanyi, A., Papp, Z., Jakab, L., Tury, E., 1995b. Effect of various levels of

T-2 toxin in the immune system of growing pigs. Vet. Rec. 136, 511–514.

Raju, M.V., Devegowda, G., 2000. Influence of esterified-glucomannan on performance and organ morphology,

serum biochemistry and haematology in broilers exposed to individual and combined mycotoxicosis (aflatoxin,

ochratoxin and T-2 toxin). Br. Poult. Sci. 41, 640–650.

Richard, J.L., Cysewski, S.J., Pier, A.C., Booth, G.D., 1978. Comparison of effects of dietary T-2 toxin on growth,

immunogenic organs, antibody formation, and pathologic changes in turkeys and chickens. Am. J. Vet. Res.

39, 1674–1679.

Richter, W.I.F., 1989. Investigations of vomitoxin (deoxynivalenol) contaminated diets fed to growing-finishing

pigs. Wirtschaftseigene Futter 35, 126–136.Rizzo, A.F., Atroshi, F., Ahotupa, M., Sankari, S., Elovaara, E., 1994. Protective effect of antioxidants against free

radical-mediated lipid peroxidation induced by DON or T-2 toxin. J. Vet. Med. A: Physiol. Pathol. Clin. Med.

41, 81–90.

Rotter, B.A., Thompson, B.K., Prelusky, D.B., Trenholm, H.L., 1991. Evaluation of potential interactions involving

trichothecene mycotoxins using the chick embryotoxicity bioassay. Arch. Environ. Contam. Toxicol. 21, 621–

624.

Rotter, R.G., Thompson, B.K., Trenholm, H.L., Prelusky, D.B., Hartin, K.E., Miller, J.D., 1992. A preliminary

examination of potential interactions between deoxynivalenol (DON) and other selected Fusarium metabolites

in growing pigs. Can. J. Anim. Sci. 72, 107–116.

Rotter, B.A., Thompson, B.K., Lessard, M., Trenholm, H.L., Tryphonas, H., 1994. Influence of low-level exposure

to Fusarium mycotoxins on selected immunological and hematological parameters in young swine. Fundam.Appl. Toxicol. 23, 117–124.

Rotter, B.A., Thompson, B.K., Lessard, M., 1995. Effects of deoxynivalenol-contaminated diet on performance

and blood parameters in growing swine. Can. J. Anim. Sci. 75, 297–302.




Rotter, B.A., Prelusky, D.B., Pestka, J.J., 1996. Toxicology of deoxynivalenol (vomitoxin). J. Toxicol. Environ.

Health 48, 1–34.

SCF(Scientific Committee forFood), 1999. Opinion on Fusarium toxins. Part1. Deoxynivalenol(DON) (expressed

on 2 December 1999), http://europa.eu.int/comm/food/fs/sc/scf/out44 en.pdf . Accessed 3 February 2002.SCF (Scientific Committee for Food), 2000. Opinion on Fusarium toxins. Part 4. Nivalenol (expressed on 19

October 2000), http://europa.eu.int/comm/food/fs/sc/scf/out74 en.pdf . Accessed 3 February 2002.

SCF (Scientific Committee forFood), 2001. Opinion on Fusarium toxins. Part 5. T-2toxin and HT-2 toxin (adapted

on 30 May 2001), http://europa.eu.int/comm/food/fs/sc/scf/out88 en.pdf . Accessed 3 February 2002.

SCF (Scientific Committee for Food), 2002. Opinion on Fusarium toxins. Part 6. Group evaluation of T-2 toxin,

HT-2 toxin, nivalenol and deoxynivalenol (adapted on 26 February 2002), http://europa.eu.int/comm/food/fs/

sc/scf/out123 en.pdf .

Schuh, M., 1982. The importance of fusariotoxicoses in Austrian domstic animals. In: Proceedings of the Animal

Production, Uppsala, pp. 390–394.

Smith, T.K., MacDonald, E.J., 1991. Effect of fusaric acid on brain regional neurochemistry and vomiting behavior

in swine. J. Anim. Sci. 69, 2044–2049.

Smith, T.K., McMillan, E.G., Castillo, J.B., 1997. Effect of feeding blends of Fusarium mycotoxin-contaminatedgrains containing deoxynivalenol and fusaric acidon growth and feed consumption of immature swine. J. Anim.

Sci. 75, 2184–2191.

Speers, G.M., Mirocha, C.J., Christensen, C.M., Behrens, J.C., 1977. Effects on laying hens of feeding corn

invaded by two species of Fusarium and pure T-2 mycotoxin. Poult. Sci. 56, 98–102.

Swanson, S.P., Corley, R.A., 1989. The distribution, metabolism, and excretion of trichothecene mycotoxins. In:

Beasley, V.R. (Ed.), Trichothecene Mycotoxicosis Pathophysiologic Effects, vol. I. CRC Press, Boca Raton,

pp. 37–61.

Swanson, S.P., Helaszek, C., Buck, W.B., Rood Jr., H.D., Haschek, W.M., 1988. The role of intestinal microflora

in the metabolism of trichothecene mycotoxins. Food Chem. Toxicol. 26, 823–829.

Terao, K., Kera, K., Yazima, T., 1978. The effects of trichothecene toxins on the Bursa of Fabricius in day-old

chicks. Virchows Arch. B: Cell Pathol. 27, 359–370.

Thompson, W.L., Wannemacher, R.W., 1986. Structure–function relationships of 12,13-epoxytrichothecenemycotoxins in cell culture: comparison to whole animal lethality. Toxicon 24, 985–994.

Thuvander, A., Wikman, C., Gadhasson, I., 1999. In vitro exposure of human lymphocytes to trichothecenes:

individual variation in sensitivity and effects of combined exposure on lymphocyte function. Food Chem.

Toxicol. 37, 639–648.

Tobias, S., Rajic, I., Vanyi, A., 1992. Effect of T-2 toxin on egg production and hatchability in laying hens. Acta

Vet. Hung. 40, 47–54.

Trenholm, H.L., Cochrane, W.P., Cohen, H., Elliot, J.I., Farnworth, E.R., Friend, D.W., Hamilton, R.M., Standish,

J.F., Thompson, B.K., 1983. Survey of vomitoxin contamination of 1980 Ontario white winter wheat crop:

results of survey and feeding trials. J. Assoc. Off. Anal. Chem. 66, 92–97.

Trenholm, H.L., Thompson, B.K., Hartin, K.E., Greenhalgh, R., McAllister, A.J., 1985. Ingestion of vomitoxin

(deoxynivalenol)-contaminated wheat by nonlactating dairy cows. J. Dairy Sci. 68, 1000–1005.

Trenholm, H.L., Friend, D.W., Thompson, B.K., Prelusky, D.B., 1988. Effects of zearalenone and deoxynivalenol

combinations fed to pigs. Proc. Jpn. Assoc. Mycotox. (Suppl. 1), 101–102.

Trenholm, H.L., Foster, B.C., Charmley, L.L., Thompson, B.K., Hartin, K.E., Coppock, R.W., Albassam, M.A.,

1994. Effects of feeding diets containing Fusarium (naturally) contaminated wheat or pure deoxynivalenol

(DON) in growing pigs. Can. J. Anim. Sci. 74, 361–369.

Vanyi, A., Glavits, R., Gajdacs, E., Sandor, G., Kovacs, F., 1991. Changes induced in newborn piglets by the

trichothecene toxin T-2. Acta Vet. Hung. 39, 29–37.

Vesonder, R.F., Ciegler, A., Jensen, A.H., 1973. Isolation of the emetic principle from Fusarium-infected corn.

Appl. Microbiol. 26, 1008–1010.

Weaver, G.A., Kurtz, H.J., Bates, F.Y., Chi, M.S., Mirocha, C.J., Behrens, J.C., Robison, T.S., 1978a. Acute and

chronic toxicity of T-2 mycotoxin in swine. Vet. Rec. 103, 531–535.

Weaver, G.A., Kurtz, H.J., Mirocha, C.J., Bates, F.Y., Behrens, J.C., Robinson, T.S., Gipp, W.F., 1978b.Mycotoxin-induced abortions in swine. Can. Vet. J. 19, 72–74.

Weaver, G.A., Kurtz, H.J., Mirocha, C.J., Bates, F.Y., Behrens, J.C., Robison, T.S., 1978c. Effect of T-2 toxin on

porcine reproduction. Can. Vet. J. 19, 310–314.

http://europa.eu.int/comm/food/fs/sc/scf/out44_en.pdf










WHO, 1990. Selected mycotoxins: Ochratoxins, Trichothecenes, Ergot. Environmental Health Criteria 105,

Geneva.

Williams, K.C., Blaney, B.J., 1994. Effect of the mycotoxins, nivalenol and zearalenone, in maize naturally

infected with Fusarium graminearum on the performance of growing and pregnant pigs. Aust. J. Agric. Res.45, 1265–1279.

Williams, K.C., Blaney, B.J., Magee, M.H., 1988. Responses of pigs fed wheat naturally infected with Fusarium

graminearum and containing the mycotoxins 4-deoxynivalenol and zearalenone. Aust. J. Agric. Res. 39, 1095–

1105.

Williams, K.C., Blaney, B.J., Dodman, R.L., Palmer, C.L., 1992a. Assessment for animal feed of maize kernels

naturally-infected predominantly with Fusarium moniliforme and Diplodia maydis. I. Fungal isolations and

changes in chemical composition. Aust. J. Agric. Res. 43, 773–782.

Williams, K.C., Blaney, B.J., Young, R.A., Peters, R.T., 1992b. Assessment for animal feed of maize kernels

naturally infected predominantly with Fusarium moniliforme and Diplodia maydis. II. Nutritive value as

assessed by feeding to rats and pigs. Aust. J. Agric. Res. 43, 783–794.

Williams, K.C., Blaney, B.J., Peters, R.T., 1994. Pigs fed Fusarium-infected maize containing zearalenone and

nivalenol with sweeteners and bentonite. Livest. Prod. Sci. 39, 275–281.Wyatt, R.D., Weeks, B.A., Hamilton, P.B., Burmeister, H.R., 1972. Severe oral lesions in chickens caused by

ingestion of dietary fusariotoxin T-2. Appl. Microbiol. 24, 251–257.

Wyatt, R.D., Colwell, W.M., Hamilton, P.B., Burmeister, H.R., 1973a. Neural disturbances in chickens caused by

dietary T-2 toxin. Appl. Microbiol. 26, 757–761.

Wyatt, R.D., Hamilton, P.B., Burmeister, H.R., 1973b. The effects of T-2 toxin in broiler chickens. Poult. Sci. 52,

1853–1859.

Wyatt, R.D., Doerr, J.A., Hamilton, P.B., Burmeister, H.R., 1975a. Egg production, shell thickness, and other

physiological parameters of laying hens affected by T-2 toxin. Appl. Microbiol. 29, 641–645.

Wyatt, R.D., Hamilton, P.B., Burmeister, H.R., 1975b. Altered feathering of chicks caused by T-2 toxin. Poult.

Sci. 54, 1042–1045.

Yagen, B., Bialer, M., 1993. Metabolism and pharmacokinetics of T-2 toxin and related trichothecenes. Drug

Metab. Rev. 25, 281–323.

Young, L.G., McGirr, L., Valli, V.E., Lumsden, J.H., Lun, A., 1983. Vomitoxin in corn fed to young pigs. J. Anim.

Sci. 57, 655–664.

Documents

sine Toxins