Saccharin, first synthesized in 1879, eventually became popular as an inexpensive substitute for sugar, particularly as a non-caloric sweetner. The dispute concerning the safety of saccharin for human consumption is almost as old as saccharin itself. In this article, the history concerning the uses of saccharin and the accompanying controversy are reviewed. In addition, the spectrum of toxicological and epidemiological studies to which saccharin has been subjected are also examined. While the toxicological data indicate that saccharin is probably the agent solely responsible for the bladder tumors observed in second generation male rats, the epidemiological studies provide, at best, an equivocal relationship between the consumption of saccharin and bladder cancer. A benefit-risk evaluation for saccharin showed few, if any documentable benefits from the use of saccharin and much genuine uncertainty concerning the potential risks for ingestion by man. This element of genuine uncertainty as to the extent of human risk posed to man is the crux of saccharin's past and its foreseeable future.

Animals↗

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A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives.

This review describes a procedure for the safety evaluation of flavouring substances. Over 2500 flavouring substances are currently in use in food. While toxicity data do not exist on all flavouring substances currently in use, within structurally related groups of flavouring substances many do have toxicity data and this information along with knowledge of structure-activity relationships and data on the daily intake provides a framework for safety evaluation. The safety evaluation procedure provides a scientifically based practical method of integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances in a timely manner. The procedure has been used recently by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) to evaluate a total of 263 flavouring substances.

Flavoring Agents↗

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Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC monographs.

The IARC Monographs (Vols 1-70) were studied to determine the time of onset of treatment-related tumorigenicity in long-term rodent studies for chemicals classified by IARC as having sufficient evidence of carcinogenicity in animals. The analysis excluded studies on metals and their salts, studies on particulates, studies by parenteral routes of administration that resulted in tumours only at the site of exposure, and studies that did not approximate to the current standard long-term rodent carcinogenicity bioassay, for instance transplacental or multigeneration studies, initiator-promoter studies, lung tumour assays in Strain A mice and studies in newborn animals. Data from a total of 210 chemicals revealed that, overall, evidence of treatment-related tumorigenicity was first apparent within 12 months for 66% of the chemicals and for only 7% were studies of longer than 18 months necessary. All IARC Group 1 chemicals were detected in animals within 18 months, and most within 12 months. Most of the tumour types that required more than 18 months for detection were of dubious relevance to human risk assessment. Termination of rodent carcinogenicity studies at 18 months or earlier would greatly reduce the complications that arise in interpreting the findings in aged animals which often have defective hepatic or renal function and would also markedly reduce the time required for histopathological examination of dozens of tissues taken from the approximately 500 animals routinely employed in these studies.

Animals↗

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Thresholds of toxicological concern based on structure-activity relationships.

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Consumer Product Safety↗

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Considerations in chronic toxicity testing: the chemical, the dose, the design.

Rodent bioassay systems are widely used to detect those environmental substances most likely to be carcinogenic. Experience with these systems has revealed several shortcomings of an operational nature which may complicate evaluation and interpretation of the results. Paramount among these are purity of the test chemical, dose selection, and experimental design. Special attention must be given to potential impurities in test substances which may be responsible wholly or in part for the production of toxic effects. Proposals for handling this problem are discussed. It is recommended that test chemicals be studied carefully in the proposed animal species using pharmacokinetic procedures, so that doses may be selected that will not jeopardize the outcome of the test nor overload metabolic detoxification systems. Whether or not a bigenerational exposure is required to adequately evaluate the carcinogenicity of the test substance will depend upon its use pattern and pharmacokinetic and metabolic behavior in the mother and fetus.

Animals↗

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Chronic toxicity of methylmercury in the rat.

Groups of 50 male and 50 female Wistar rats were fed diets containing methylmercuric chloride to provide daily doses of 0, 0.002, 0.010, 0.050 and 0.250 mg Hg/kg/day for up to 26 months. Food consumption, and body weight measurements were monitored weekly on all rats. Hematological examinations were done at 0, 6, 12, 15 and 17 months of treatment. Histopathologic examination and analysis for total mercury levels were performed terminally. Male rats receiving 0.25 mg Hg/kg/day had decreased body weights, decreased hematocrit and hemoglobin values, overt clinical signs of neurotoxicity and increased mortality compared to controls. Female rats receiving 0.25 mg Hg/kg/day had decreased body weights and minimal clinical signs of neurtoxicity. Histopathological examination revealed demyelination of the dorsal nerve roots and peripheral nerves, severe kidney damage and decreased basophilia of hepatocytes in male rats receiving 0.25 mg Hg/kg/day. Male rats receiving 0.05 mg Hg/kg/day had minimal renal damage. Female rats receiving 0.25 mg Hg/kg/day had demyelination of the dorsal nerve roots and peripheral nerves and minimal renal damage. No histopathological lesions were observed in the female rats receiving 0.05 mg Hg/kg/day and in male and female rats in the other dose groups.

Animals↗