Aldehydes constitute a group of relatively reactive organic compounds. They occur as natural (flavoring) constituents in a wide variety of foods and food components, often in relatively small, but occasionally in very large concentrations, and are also widely used as food additives. Evidence of carcinogenic potential in experimental animals is convincing for formaldehyde and acetaldehyde, limited for crotonaldehyde, furfural and glycidaldehyde, doubtful for malondialdehyde, very weak for acrolein and absent for vanillin. Formaldehyde carcinogenesis is a high-dose phenomenon in which the cytotoxicity plays a crucial role. Cytotoxicity may also be of major importance in acetaldehyde carcinogenesis but further studies are needed to prove or disprove this assumption. For a large number of aldehydes (relevant) data on neither carcinogenicity nor genotoxicity are available. From epidemiological studies there is no convincing evidence of aldehyde exposure being related to cancer in humans. Overall assessment of the cancer risk of aldehydes in the diet leads to the conclusion that formaldehyde, acrolein, citral and vanillin are no dietary risk factors, and that the opposite may be true for acetaldehyde, crotonaldehyde and furfural. Malondialdehyde, glycidaldehyde, benzaldehyde, cinnamaldehyde and anisaldehyde cannot be evaluated on the basis of the available data. A series of aldehydes should be subjected to at least mutagenicity, cytogenicity and cytotoxicity tests. Priority setting for testing should be based on expected mechanism of action and degree of human exposure.

Aldehydes↗

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Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode 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 4-wk feeding study, lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene and d-limonene, each affecting renal proximal tubular cells but through different modes of action, were administered simultaneously at their individual lowest-observed-nephrotoxic-effect level (LONEL), no-observed-nephrotoxic-effect level (NONEL) and NONEL/4. Combined exposure at the LONEL resulted in increased growth depression and increased renal toxicity in male but not in female rats. Co-exposure at the NONEL produced only weak signs of toxicity (slightly retarded growth and increased renal weight), and rats co-exposed at the NONEL/4 did not show any treatment-related changes. The absence of an obviously increased hazard on combined exposure at the NONEL suggested absence of synergism and probably also of additivity. In a subsequent study the additivity assumption (dose addition) was tested, using the similarly acting nephrotoxicants tetrachloroethylene, trichloroethylene, hexachloro-1,3-butadiene and 1,1,2-trichloro-3,3,3-trifluoropropene. The compounds were given to female rats by daily oral gavage for 32 days either alone, at the LONEL and NONEL (= LONEL/4), or in combinations of four (at the NONEL and LONEL/2) or three (at the LONEL/3). Relative kidney weight was increased on exposure to the individual compounds at their LONEL and, to about the same extent, on combined exposure at the NONEL or the LONEL/3. As assessed by this endpoint, the renal toxicity of the mixtures corresponded to the effect expected on the basis of the additivity assumption. The other endpoints were not (or hardly) affected on combined exposure.

Administration, Oral↗

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Use of factorial designs in combination toxicity studies.

The use of factorial designs, in which n chemicals are studied at xn dose levels (x treatment groups), has been put forward as one of the valuable statistical approaches for hazard assessment of chemical mixtures. Very recently a "2(5) study' was presented to describe interactions between the carcinogenic activity of five polycyclic aromatic hydrocarbons and a "5(3) study' was used to identify the non-additive effects of three compounds on developmental toxicity. Full factorial designs, however, lead to very costly experiments and, even if only two dose levels are used, it is not always possible to perform conventional toxicity tests using 2n test groups to identify possible interactions between all chemicals of interest. One way to deal with this problem is the use of fractionated factorial designs. These fractionated designs still identify most of the interactions between the compounds and determine which compounds are important in causing effects, but have the advantage that the number of test groups is manageable. Fractional factorial designs have been shown to be an efficient (i.e. cost-effective) approach to: (a) identify interactive effects between seven trace elements and cadmium accumulation in the body; and (b) describe cases of non-additivity in a mixture of nine chemicals tested in a 4-wk toxicity study in rats.

Administration, Oral↗

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Complex mixtures: hazard identification and risk assessment.

Regarding risk evaluation of complex mixtures, the Working Group discussed the following topics: evaluation of the mixture as a whole, fractionation of the mixture, identification of the 'top ten' chemicals, and composite standards. It was concluded that no standard methodology for hazard identification and risk assessment of complex mixtures yet exists, but assessment of complex mixtures must proceed, using all available information, methods, technology, expertise and experience. The development of a decision tree for tackling complex mixtures was recommended, and the need to move forward with instituting standards for mixtures, especially in job-oriented situations, was emphasized.

Chemical Fractionation↗

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Toxicology of sulphiting agents. I: Animal studies.

Oral toxicity studies of sulphite in animals are briefly reviewed. On the basis of a chronic toxicity/carcinogenicity study of sodium metabisulphite in rats JECFA established an ADI of 0.7 mg SO2/kg using a safety factor of 100. The effects of sodium metabisulphite (1% Na2S2O5) on the composition of semi-purified rat diets during storage for at least three months have been studied. Under these conditions sulphite induced rancid off-flavours in diets containing unsaturated fats. The feeding of such stored sulphited-diets to rats resulted in growth retardation and diminished food efficiency. The extractability of the lipids from these diets was markedly reduced. Extraction with hexane, followed by ethanol extraction did not remove the toxic factor(s). It was suggested that sulphite in stored semi-purified diets may react with unsaturated fats leading to the formation of polymers of unsaturated fatty acids and/or other toxic substances. It is recommended that special attention is paid to the fatty acid composition of sulphited foods to be stored.

Animals↗

PubMedDate not supplied

Polyethylene terephthalate bottles (PRBs): a health and safety assessment.

As part of a multi-client project, the potential public health risks of the reuse of polyethylene terephthalate (PET) refillable bottles (PRBs) following possible misuse has been investigated. Participants in the project provided data and information from previous studies conducted independently at contract laboratories. These studies were sponsored by the clients in order to provide further research data on PET containers and their safety. In this report, the results of five of these studies along with the results of a recent study carried out at TNO are compiled and reported. PET refillable bottles were exposed to 62 contaminants, including pesticides, that a consumer could potentially store in bottles. After storage with a contaminant under well defined conditions, the bottles were washed, filled with a simulated beverage, and stored for various lengths of time. The beverage and in some cases the bottle wall were then analysed for the presence of the contaminants. Toxicological evaluation of the analytical results from these tests on contaminant residue remigration showed that even under exaggerated exposure conditions, there was no public health concern. Only one compound, parathion, remigrated to a level that required a more in-depth risk evaluation, and under the most conservative assumptions, it too presented no real health hazard. Additionally, current detection systems employed to ensure product quality detect a wide variety of contaminants, including commercial formulations of parathion. Data developed in this paper are consistent with the finding that PRBs can be safely reused. For preventing negative effects on product quality (e.g. taste), however, good manufacturing procedures including visual and electronic inspection systems are required to eliminate abused bottles.

Animals↗

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Approach to setting occupational exposure limits for sensory irritants in The Netherlands.

This article describes how scientists in the Netherlands set occupational exposure limits (OELs) for sensory irritants. When they tackle this issue, a number of key questions need to be answered. For example, did the studies indeed measure sensory irritation and not cytotoxicity? When the irritant is an odorant, can interference of olfactory stimulation be excluded? In the case of subjective measurements, can psychological irritation be excluded? When adaptation is an issue, did the studies indeed measure adaptation and not habituation? When OELs are established in the Netherlands, each of these issues is carefully addressed before a value is suggested. When setting an OEL in the Netherlands, human data carry more weight than animal data of comparable quality. As in the United States, documentation for the recommended OEL is written and a discussion of all available relevant and reliable data culminating in the selection of the key study for deriving the health-based recommended occupational exposure limit is provided. Special effort is dedicated to reconciling differences between the animal and human data. If the toxicological database is considered to be inadequate, the committee acknowledges this limitation and will not recommend a limit value due to insufficient data.

Air Pollutants, Occupational↗

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Safety evaluation of chemical mixtures and combinations of chemical and non-chemical stressors.

Recent developments in hazard identification and risk assessment of chemical mixtures are reviewed. Empirical, descriptive approaches to study and characterize the toxicity of mixtures have dominated during the past two decades, but an increasing number of mechanistic approaches have made their entry into mixture toxicology. A series of empirical studies with simple chemical mixtures in rats is described in some detail because of the important lessons from this work. The development of regulatory guidelines for the toxicological evaluation of chemical mixtures is discussed briefly. Current issues in mixture toxicology include the adverse health effects of ambient air pollution; the application of such modern, sophisticated methodologies as genomics, bioinformatics, and physiologically based pharmacokinetic modeling; and databases for mixture toxicity. Finally, the state of the art of our knowledge on the potential adverse health effects of combined exposures to chemicals and non-chemical stressors (noise, heat/cold, microorganisms, immobilization, restraint, or transportation), research initiatives in these fields, and the development of an indicator for the cumulative health impact of multiple environmental exposures are discussed.

Dose-Response Relationship, Drug↗

PubMedDate not supplied

One-year time-sequence inhalation toxicity study of vinyl chloride in rats. II. Morphological changes in the respiratory tract, ceruminous glands, brain, kidneys, heart and spleen.

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Animals↗

PubMedDate not supplied

One-year time-sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver.

Wistar rats were exposed to atmospheres containing 0 (control) or 5000 ppm vinyl chloride monomer (VCM), 7 h/day, 5 days/week, for a period of 52 weeks. After 4, 13, 26 and 52 weeks each time 10 rats/sex/group were killed and subjected to extensive examinations. The present paper describes the morphological changes found in the liver. The major parenchymal changes comprised swelling and malformation of mitochondria, an increased amount of smooth endoplasmic reticulum, necrosis, nuclear and cellular polymorphism of hepatocytes, "foci of cellular alteration", neoplastic nodules and hepatocellular carcinomas. A reduced glucose-6-phosphatase activity in hepatocytes and a strong sinusoidal activity of alkaline phosphatase were found within "foci of cellular alteration". The non-parenchymal alterations included focal dilatation of sinusoids, focal proliferation of atypical sinusoidal cells and multicentric angiosarcomas. The effects of VCM on the hepatic parenchyma seemed to precede those on the hepatic stroma.

Animals↗