Toxicology of chemical mixtures: challenges for today and the future

Feron, V.J.; Groten, J.P.; Jonker, D.; Cassee, Flemming R.; Bladeren, P.J. van

doi:10.1016/0300-483x(95)03239-c

Cited by 58 publications

(27 citation statements)

References 22 publications

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“…In acute and subacute toxicity studies in rats it has been shown that combined oral administration of compounds at the "no-observed-adverse-effect level" (NOAEL) of each of them did not lead to clear additivity or synergism of effects, provided the mechanism of action of the compounds was dissimilar (Jonker et al, 1990(Jonker et al, , 1993. In contrast, in a 4-week toxicity study with mixtures consisting of four nephrotoxicants with similar mode of action, it was shown that the dose-additivity rule could be applied (Feron et al, 1995b) at dose levels around the NOAEL. These 4-week toxicity studies were interpreted based on the common approaches in the assessment of mixtures; for a combination of compounds with a similar mode of action, one might expect dosis-addition, whereas compounds with a dissimilar mode of action may show effect addition (Bliss, 1939;Placket and Hewlett, 1952;Mumtaz et al, 1994).…”

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confidence: 98%

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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mentioning

confidence: 98%

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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“…But to undertake a full toxicological assessment of even a single chemical would cost several million pounds. While this may be justified for such common and commercially important chemicals as formaldehyde it is clearly out of the question to investigate every pollutant in this thorough manner let alone to undertake investigations of combinations of pollutants [89]. There is also the insurmountable problem of extrapolation of experimental data obtained using high concentrations in homogeneous populations of animals to the effects of low concentrations in diverse populations of humans.…”

Section: Amelioration Of Riskmentioning

confidence: 99%

Health Risks from Indoor Air Pollutants: Public Alarm and Toxicological Reality

Leslie¹

2000

Indoor Built Environ

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The air, particularly the indoor air, contains a considerable burden of unwanted pollution. Overall there may be thousands of pollutants. They are brought in with the outside air or are generated from or within buildings. Most will be present in minute amounts but several will be present in measurable quantities. The reaction of people to the components of this pollution has little to do with toxicological assessment but is more concerned with political responses and media scares. The health effects from exposure to the very low levels commonly found in the indoor environment of materials such as combustion products, whether from coal, petrol or tobacco or to lead or asbestos fibres, are probably negligible but we worry about them. On the other hand, gases such as carbon monoxide or nitrogen dioxide which are not infrequently present in dangerous concentrations, many solvents and dust-generating DIY projects cause little concern. The distinction between concern and indifference is made without reference to any toxicological knowledge. Although it is certainly prudent, through source control, design and ventilation of buildings, to reduce all pollutants to the lowest level, concentrating on media favourites rather than more important dangers, including disease transmission, may well be a poor use of our resources.

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“…For example, combined exposure to pesticides and heavy metals is known to enhance overall toxicity compared with that from exposure to the individual agents (Institoris et al, 1999(Institoris et al, , 2002. Approaches to assess effects from combined exposures have been described (Feron et al, 1995;Groten et al, 2001;Hernandez et al, 2013;Simmons, 1995). However, most toxicity assessments are conducted based on exposure to individual substances and, as such, mechanisms of effects from combined exposure to environmental chemicals remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of short-term oral combined exposure to environmental immunotoxic chemicals in mice

Nishino

Fukuyama

Kosaka

et al. 2013

Journal of Immunotoxicology

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People are constantly exposed to environmental chemicals through contact with the atmosphere or by ingestion of food. Therefore, when conducting safety assessments, the immunotoxic effects of combinations of chemicals in addition to toxicities produced by each chemical alone should be considered. The objective of the studies reported here were to demonstrate the combined effects of three well-known environmental immunotoxic chemicals -methoxychlor (MXC), an organochlorine compound; parathion (PARA), an organophosphate compound; and piperonyl butoxide (PBO), an agricultural insecticide synergist -by using a short-term oral exposure method. Seven-week-old Balb/cAnN mice received daily oral exposure to either one or two of the environmental immunotoxic chemicals for 5 consecutive days. On Day 2, all mice in each group were immunized with sheep red blood cells (SRBC), and their SRBC-specific IgM responses were analyzed by using an enzyme-linked immunosorbent assay and plaque-forming cell assay. T-and B-cell counts in the mouse spleens were also assessed via surface antigen expression. Mice that received MXC þ PARA and PBO þ MXC treatment showed marked decreases in SRBC-specific IgM production and T-and B-cell counts compared with those in mice that received vehicle control or the corresponding individual test substance. This suggests that simultaneous exposure to multiple environmental chemicals increases the immunotoxic effects of the chemicals compared to individual exposure.

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Toxicology of chemical mixtures: challenges for today and the future

Cited by 58 publications

References 22 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

Health Risks from Indoor Air Pollutants: Public Alarm and Toxicological Reality

Effects of short-term oral combined exposure to environmental immunotoxic chemicals in mice

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