Combined Actions and Interactions of Chemicals in Mixtures

octyltin dichloride). A number of adverse effects seen at the LOAEL, such as
decreased prothrombin time, increased liver enzyme activity (ALAT and ASAT) in
plasma, increased kidney weights, reduced number of corpora lutea in ovaries, and
increased numbers of multinucleated giant cells in the epididymides had not been
seen at all or had been found at doses higher than the LOAEL of the individual
compounds. Although some of these changes may be related to the severe growth
retardation, they suggested some kind of interaction resulting in a slightly more
severe and maybe broader range of toxic response. On the other hand the changes
in the thymus were less pronounced on combined exposure than after exposure to
di-n-octyltin dichloride alone, suggesting interaction leading to less severe toxicity.
Table 5.2.1. Toxicological studies of chemicals with different target organs and/or modes of
action.
Compound
Potassium
nitrate
Stannous
chloride
Sodium
metabisulphiteMetalde-
hyde
62
NOAEL/10 NOAEL/3 NOAEL LOAEL
Mg/kg bw/day
Target
organ
10 33 100 300 Adrenals
100 330 1000 3000 Body
weight,
blood, liver
500 1670 5000 20000 Blood,
stomach,
liver
20 70 200 1000 Liver
Loperamide 0.5 1.7 5 25 Body weight
Mirex 0.5 1.7 5 80 Body
weight, liver
blood
Lysino- 3 10 30 100 Kidneys
alanine
Di-n-octyltin
dichloride
0.6 2 6 30 Thymus,
liver
The authors concluded that the study demonstrates absence of a simple additive
effect and synergism, and provides some, but no convincing evidence for an
increased risk from exposure to a combination of chemicals when each chemical is
administered at its own individual NOAEL. At lower dose levels no increased risk
appeared to exist.
The other experiment (Feron et al. 1995a, Groten et al. 1997) was a 4-week
oral/inhalatory study in male Wistar rats in which the toxicity of combinations of
nine compounds was examined (Table 5.2.2). In this study a combination was used
of compounds highly relevant to the general population in terms of use patterns and
levels and frequency of exposure. The study included 20 experimental groups, four
groups of eight rats in the main study and 16 groups of five rats in a satellite study.
In the main study, the rats were simultaneously exposed to mixtures of all nine
chemicals. Dichloromethane and formaldehyde were administered by inhalation
and aspirin, di(2- ethylhexyl)phthalate (DEHP), cadmium chloride, stannous
chloride, butyl hydroxyanisol (BHA), loperamide, and spermine were given in the
diet at concentrations equal to the "minimum-observed-adverse-effect level"
(LOAEL), the NOAEL, or one third the NOAEL. The satellite study was designed
as a fractionated two-level factorial study in which the rats were simultaneously
exposed to combinations of maximally five compounds at their LOAEL. These 16