Safety evaluation of the mixture of chemicals at a specific workplace: theoretical considerations and a suggested two-step procedure

Feron, V.J.; Woutersen, Ruud; Arts, J.H.E.; Cassee, Flemming R.; Vrijer, Flora de; Bladeren, P.J. van

doi:10.1016/0378-4274(94)03193-2

Cited by 22 publications

(18 citation statements)

References 28 publications

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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.…”

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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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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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“…Few mixed-exposure OELs have been established, because assessment methods for mixed exposures have been based on extrapolation rather than direct toxicological data [Mumtaz et al 1995]. The current challenge for environmental and occupational scientists is to provide a sound, scientific basis that enables policymakers to substitute current, simplistic, single-chemical standard setting with real-life, mixture-oriented standard setting [Feron et al 1995].…”

Section: Development Of Oebs For Mixed Exposuresmentioning

confidence: 99%

Technical report: the NIOSH occupational exposure banding process for chemical risk management.

Lentz¹,

Seaton²,

Rane³

et al. 2019

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“…Collaboration between scientists, engineers, management, workers, and others is needed for identifying and ranking exposure hazards. Use of such approaches has been described in the litera-ture [Anderson-Murawski et al 2002;Feron et al 1995b].…”

Section: Identifying Mixture Hazardsmentioning

confidence: 99%

“…Another strategy is to prioritize a larger but still limited list of exposures and use a range of experimental protocols to verify the assumptions of additivity or independence of effects of the exposure combinations [Feron 1995b]. This is primarily a prioritization strategy; most, if not all, of the other strategies described in this section could be applied to the list of exposures.…”

Section: Research Organized Around Prioritized Lists Of Exposuresmentioning

confidence: 99%

Mixed exposures research agenda - a report by the NORA Mixed Exposures Team.

2004

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Safety evaluation of the mixture of chemicals at a specific workplace: theoretical considerations and a suggested two-step procedure

Cited by 22 publications

References 28 publications

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

Technical report: the NIOSH occupational exposure banding process for chemical risk management.

Mixed exposures research agenda - a report by the NORA Mixed Exposures Team.

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