67
Combination effects of multiple residues as
exemplified by azole fungicides
Assessing the health risks of multiple residues of pes-
ticides presents a challenge as, although sufficient
toxicological data are present for the individual active
substances, there have been relatively few experimental
studies into possible combination effects.
To contribute to the experimental studies into this sub-
ject, a research project was carried out in the BfR with
a frequently used group of active substances, the azole
fungicides. The tested substances were first examined
individually and then in different combinations, in a wide
dose range, on both rats and specific cell lines. The main
focus of the test was the liver, the main target organ of
these fungicides. In the rat feeding studies, the results
Change in relative liver weight of rats following administration of the azole fungicides cyproconazole, epoxiconazole and
prochloraz individually and in two different combinations, over a wide dose range, compared to control groups. NOAEL
stands for “no observed adverse effect level”. It is based on corresponding observations made by regulatory studies into
the relevant substances. The dose range varied from the NOAEL divided by 100 to the NOAEL multiplied by 10. Changes
were only observed for the highest dose (* statistically significant with p < 0.01 in Mann Whitney U Test).
show that combination effects were present only in dos-
ages where the individual substances also had an effect.
They were merely more pronounced in some cases.
As an example, the figure below shows a result from the
aforementioned 28-day study of rats. The weight of the
rats' livers only changed significantly compared to the
control group when they received high doses of the fun-
gicides. Liver weight following the administration of multi-
ple substances was only marginally more elevated than it
was following treatment with individual active substances.
For the assessment of combination effects, the data
prove that a simple additivity of the effects of various
substances on the same organ provides sufficient pro-
tection. The EFSA, among others, also argues in favour of
this so-called dose additivity assessment principle.
Findings of the BfR research project: Combination Effect of Azole Fungicides
*
* * * *
cyproconazole
Controls
NOAEL/100
NOAEL
NOAELx10
epoxiconazole
prochloraz
Relative liver weight (in % of body weight)
6
5
4
0
1
2
3
cyproconazole + epoxiconazole
cyproconazol + epoxiconazole + prochloraz
Chemicals Safety
