Combined Actions and Interactions of Chemicals in Mixtures

seen in the animals from the 1000x group with a trend towards reduced proportion
of diploid cell at that dose.
The authors concluded that the mixture induced effects on the liver and the kidney
and on the general metabolism at high doses but caused only minor effects on
immune function, reproductive hormone levels, or general indices of reproductive
function measures. The results suggest that additive or synergistic effects of
exposure to contaminants resulting in residue levels representative of contemporary
human tissue levels are unlikely to result in adverse effects on immune function or
reproductive physiology in male rats (Wade et al. 2002).
5.3 Same target organ with dissimilar or similar modes of action
5.3.1 Nephrotoxicants with dissimilar modes of action
The toxicity of mixtures of chemicals with the same target organ was examined in
rats using nephrotoxicants with similar or dissimilar modes of action. In a fourweek
feeding study groups of 10-week old male and female rats were administered
lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene (HCBD) and dlimonene,
each affecting renal proximal tubular cells but through different modes
of action. The nephrotoxicity of HCBD results from initial conjugation to
glutathione followed by several metabolic processes to produce a β-lyase activated
and cytotoxic metabolite while d-Limonene , via its 1,2-dioxide, produce
accumulation of the male rat-specific protein α2µ-globulin. The processes involved
in the nephrotoxicity of mercuric chloride are still poorly understood but probably
involve mitochondrial dysfunction from inhibition of enzymes and proteins by
binding to sulphhydryl groups. Lysoalanine may disturb protein functions either by
acting as a metal chelator, by incorporation in proteins, or by inhibition of lysyltRNA-synthetase.
The compounds were administered simultaneously at their
individual lowest-observed-nephrotoxic-effect level (LONEL), no-observednephrotoxic-effect
level (NONEL) and one-quarter of the NONEL (Jonker et al.
1993, Feron et al. 1995a).
Table 5.3.1.1. Toxicological studies of chemicals with the same target organ but different
modes of action.
Compound NONEL/4
(ppm in
diet)
Lysinoalanine
Mercuric
chloride
Hexachloro-
1,3-
butadiene
66
NONEL
(ppm in
diet)
LONEL
(ppm in
diet)
Mode of action
7.5 30 240 Metal ion chelator
3.75 15 120 Mitochondrial
dysfunction
5 20 100 β-Lyase mediated
activation
d-Limonene 125 500 4000 α2µ-Globulin
accumulation
The individual nephrotoxins caused slight growth depression in males at the
LONEL, but not at the NONEL, whereas the combination depressed growth
slightly at the NONEL and severely at the LONEL. In females at the LONEL, only
HCBD retarded growth; in contrast to the effect in males this was not aggravated
by combined treatment. Nephrotoxicity was more severe in males fed the
combination than in males given the nephrotoxins alone. The former showed
decreased renal concentrating ability and moderate histopathological changes in the