Subacute toxicity of a mixture of nine chemicals in rats: Detecting interactive effects with a fractionated two-level factorial design

Subacute toxicity of a mixture of nine chemicals in rats: Detecting interactive effects with a fractionated two-level factorial design

Groten, J.P.
Schoen, E.D.
van Bladeren, P.J.
Kuper, C.F.
van Zorge, J.A.
Feron, V.J.
Centraal Instituut voor Voedingsonderzoek TNO

1997

The present study was intended (1) to find out whether simultaneous administration of nine chemicals at a concentration equal to the 'no-observed-adverse-effect level' (NOAEL) for each of them would result in a NOAEL for the combination and (2) to test the usefulness of fractionated factorial models to detect possible interactions between chemicals in the mixture. A 4-week oral/inhalatory study in male Wistar rats was performed in which the toxicity (clinical chemistry, hematology, biochemistry, and pathology) of combinations of the nine compounds was examined. The study comprised 20 groups, 4 groups in the main part (n = 8) and 16 groups in the satellite part (n = 5). In the main study, the rats were simultaneously exposed to mixtures of all nine chemicals [dichloromethane, formaldehyde, aspirin, di(2-ethylhexyl)phthalate, cadmium chloride, stannous chloride, butyl hydroxyanisol, loperamide, and spermine] at concentrations equal to the 'minimum-observed-adverse-effect level' (MOAEL), NOAEL, or 1/3NOAEL. In the satellite study the rats were simultaneously exposed to combinations of maximally five compounds at their MOAEL. These combinations jointly comprise a two-level factorial design with nine factors (= 9 chemicals) in 16 experimental groups (1/32 fraction of a complete study). In the main part many effects on hematology and clinical chemistry were encountered at the MOAEL. In addition, rats of the MOAEL group showed hyperplasia of the transitional epithelium and/or squamous metaplasia of the respiratory epithelium in the nose. Only very few adverse effects were encountered in the NOAEL group. For most of the end points chosen, the factorial analysis revealed main effects of the individual compounds and interactions (cases of nonadditivity) between the compounds. Despite all restrictions and pitfalls that are associated with the use of fractionated factorial designs, the present study shows the usefulness of this type of factorial design to study the joint adverse effects of defined chemical mixtures at effect levels. It was concluded that simultaneous exposure to these nine chemicals does not constitute an evidently increased hazard compared to exposure to each of the chemicals separately, provided the exposure level of each chemical in the mixture is at most similar to or lower than its own NOAEL.

Acetylsalicylic acid
Butylated hydroxyanisole
Cadmium chloride
Dichloromethane
Formaldehyde
Loperamide
Phthalic acid bis(2 ethylhexyl) ester
Spermine
Stannous chloride
Animal experiment
Controlled study
Drug mixture
Factorial analysis
Male
Model
Nonhuman
Oral drug administration
Prognosis
Rat
Risk assessment
Theory
Toxicity
Administration, Inhalation
Animals
Blood Chemical Analysis
Body Weight
Drug Combinations
Drug Interactions
Epithelium
Hazardous Substances
Hematologic Tests
Hypertrophy
Liver
Male
Models, Statistical
Multiple Chemical Sensitivity
Nasal Cavity
No-Observed-Adverse-Effect Level
Organ Size
Rats
Rats, Wistar

http://resolver.tudelft.nl/uuid:941103fd-ec65-4487-8703-35b559363a0f

https://doi.org/10.1006/faat.1996.2281

233848

0272-0590

Fundamental and Applied Toxicology, 36 (1), 15-29

article