Subacute (4-wk) oral toxicity of a combination of four nephrotoxins in rats: comparison with the toxicity of the individual compounds

Jonker, D.; Woutersen, Ruud; Bladeren, P.J. van; Til, H.P.; Feron, V.J.

doi:10.1016/0278-6915(93)90126-j

Cited by 52 publications

(19 citation statements)

References 23 publications

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“…However, before applying the results of an interaction study to a particular risk assessment, a risk assessor should also consider the relevance of the conditions and doses used in a study to the exposure scenarios in question. Interactions that occur at high doses may not be manifested at the low environmental contaminant levels that many risk assessments must consider (Jonker et al 1990(Jonker et al , 1993Jonker et al 1996;Seed et al 1995).…”

Section: Taylor Et Al (1995)mentioning

confidence: 99%

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

Borgert

Price

Wells

et al. 2001

Human and Ecological Risk Assessment: An International Journal

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We describe a set of criteria to evaluate the quality of data and interpretations in chemical interaction studies. These criteria reflect the consensus of the literature on interaction analysis developed over decades of research in pharmacology, toxicology, and biometry; address common pitfalls in published interaction studies; and can be easily applied to common methods of interaction analysis. The criteria apply broadly to interaction data for drugs, pesticides, industrial chemicals, food additives, and natural products and are intended to assist risk assessors who must evaluate interaction studies for use in component-based mixture risk assessments. The criteria may also assist researchers interested in conducting interaction studies to inform mixture risk assessment. The criteria are also intended to serve larger scientific goals, including increasing the repeatability of results obtained in chemical interaction studies, enhancing the reliability of conclusions drawn from interaction data, providing greater consistency of interpretations among various analysts, and decreasing uncertainty in using interaction data in risk assessments. We describe the basis for each criterion and demonstrate their utility by using them to evaluate interaction studies from the recent toxicological and pharmacological literature, which serve as examples of different types of data sets that the risk assessor may encounter.

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Section: Taylor Et Al (1995)mentioning

confidence: 99%

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

Borgert

Price

Wells

et al. 2001

Human and Ecological Risk Assessment: An International Journal

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show abstract

“…Examples of this include resistance to gentamycin nephrotoxicity, which has been demonstrated in partially nephrectomized rats (11), as well as in rats recovering from acute tubular necrosis due to preexposure to tubular toxins such as mercuric chloride (42), uranyl nitrate, potassium dichromate, and glycerol (15). In addition, chronic exposure of rats to heavy metals such as cadmium, lead, inorganic mercury, or potassium dichromate does not increase toxicity resulting from subsequent exposure to gentamycin or hexachlorobutadiene (28,29,34,60).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Kirby

Bach

1995

Toxicol Pathol

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Renal damage was assessed by histopathology and urinalysis in male Wistar rats treated with either hexachloro-1:3-butadiene (HCBD; a single 170-mg/kg ip dose that caused proximal tubule necrosis), adriamycin (ADR; a single 5-mg/kg ip dose that caused minimal glomerular changes up to 35 days), or HCBD given 2 wk after ADR and compared with age-matched control rats for 21 days. Urinalysis values in ADRtreated rats showed minimal renal changes. HCBD significantly elevated urine volume (10-fold), protein (5-fold), glucose (175-fold), and brush border enzymes (10-600-fold), indicating severe proximal tubular damage, but most parameters returned to pretreatment levels 6 days after treatment. In ADR-pretreated rats subsequently given HCBD, both the urinary alkaline phosphatase and the ratio of kidney : body weight were significantly higher for longer periods. Histopathology demonstrated that the HCBD-induced proximal tubular lesion was confined to the outer stripe of the outer medulla. Advanced regeneration and repair was evident 21 days after HCBD treatment. In the ADR-pretreated rats the HCBD-induced lesion was more severe and affected the entire cortex (24).Statistics. Statistically significant differences between groups were determined by 2-tailed Students' t-test, with p < 0.05 considered to be statistically significant. RESULTS UrinanalysisThere were no significant differences in the urinary parameters in the control and ADR groups ( (Fig. 1 a). Tubules were dilated and filled with homogenous eosinophilic material and necrotic epithelial cells. Signs of regeneration and restitution (i.e., tubular re-epithelialization and loss of tubular casts and debris) were evident by day 7 and complete 21 days after treatment (Fig. 1 b).Histologically, animals in the ADR/HCBD group showed much more extensive renal damage (Fig. 2a) when compared to those treated with HCBD alone (see Fig. 1 a). Extensive tubular damage was present throughout the entire cortex 2 days after HCBD treatment, and tubules were dilated and filled with homogeneous proteinaceous material. Sloughed necrotic calcified epithelial cells were observed in tubular lumens and casts extended deep into the medulla (Fig. 2b). Extensive calcification was evident by day 7 (which was not seen in the HCBD only group) and by day 21, regeneration, although apparent, was less advanced and marked tubular calcification was still evident (Fig. 2c). Table 2 summarizes the differences between the ADR/HCBD group and HCBD alone. HistochemistryControl kidneys demonstrated normal GGT staining of the tubular epithelium of the outer stripe of the outer medulla (Fig. 3a). ADR caused no changes in this staining pattern. GGT staining in the outer stripe of the outer medulla was diminished 24 hr after HCBD treatment, was barely evident by day 3 (Fig. 3b) HCBD is a useful model toxin for damaging the proximal tubule. It is metabolized in the liver, ex-

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“…One way to overcome this problem is to treat the mixture as a single compound and to test the mixtures as a whole. This approach has been advised for mixtures that are not well characterized (Mumtaz et al, 1993), but it has also been applied for assessing the combined toxicity of defined chemical mixtures consisting of nephrotoxicants, pesticides, carcinogens, and/ or fertilizers (Jonker et al, 1993;Charturved, 1993;Heindel et al, 1994;Feron et al, 1995a;Ito et al, 1995). In these studies an experimental design was chosen, reflecting the net combined effects of all components in the mixture; to limit the number of test groups possible, interactive effects of the components in relation to the effects of individual chemicals were not taken into account.…”

mentioning

confidence: 99%

Subacute Toxicity of a Mixture of Nine Chemicals in Rats: Detecting Interactive Effects with a Fractionated Two-Level Factorial Design

Groten¹,

Schoen

BLADEREN³

et al. 1997

Toxicol Sci

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. (1997). Fundam. AppL Toxicol. 36,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] 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.

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Subacute (4-wk) oral toxicity of a combination of four nephrotoxins in rats: comparison with the toxicity of the individual compounds

Cited by 52 publications

References 23 publications

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

Evaluating Chemical Interaction Studies for Mixture Risk Assessment

Enhanced Hexachloro-1:3-butadiene Nephrotoxicity in Rats with a Preexisting Adriamycin-Induced Nephrotic Syndrome

Subacute Toxicity of a Mixture of Nine Chemicals in Rats: Detecting Interactive Effects with a Fractionated Two-Level Factorial Design

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