REGULATORY TOXICOLOGY AND PHARMACOLOGY 27, 75–81 (1998) ARTICLE NO. RT971109 Granulomas in the Livers of Humans and Fischer Rats Associated with the Ingestion of Mineral Hydrocarbons: A Comparison K. A. Fleming,* H. Zimmerman,† and P. Shubik* *Green College, at the Radcliffe Observatory, Oxford OX2 6HG, United Kingdom; and †AFIP, Washington, DC Received January 13, 1997 either naphthenic or paraffinic crude oils. Refining may be achieved by treatment with oleum or hydrogenation. Ninety-day feeding studies were conducted in Fi- In both cases, aromatics including polycyclic aromatic scher 344 rats using a series of highly refined mineral hydrocarbons which included mineral oils and waxes hydrocarbons (PAHs) and many other impurities includ- representative of those used in consumer products and ing sulfur, oxygen, and metals are removed (Hulse et food applications. The series included materials which al., 1992; Roger, 1992; Tietze, 1992). White mineral oils had been refined by oleum or hydrogenation. The ma- are complex mixtures of saturated paraffinic hydrocar- terials tested were representative of the range of car- bons (predominantly branch chain alkanes) and naph- bon chain lengths, molecular weights, and viscosities thenic hydrocarbons (alkanes containing one or more which are currently in use. Findings revealed the pres- saturated cyclic structures). Food grade paraffin waxes ence of granulomatous lesions in the liver and histio- are saturated solid hydrocarbons, predominantly linear cytosis in the lymph nodes. Some mineral hydrocar- alkanes, with varying amounts of branched and cycloal- bons did not induce any lesions; others induced rela- kanes. Microcrystalline waxes are derived from higher tively minor effects; and a low melting point wax boiling petroleum fractions and contain a higher propor- induced the largest lesions in both liver and mesen- tion of branched and cycloalkanes. teric lymph nodes, with inflammation and areas of fo- Since almost the beginning of this century there has cal necrosis in the livers. The majority of lesions re- been a continuing interest in the safety of these materi- ported were associated with the highest dose levels als to humans. Historically interest has focused on the used. These studies are in contrast to studies in potential occupational carcinogenic hazard, and this Sprague – Dawley rats in which comparable doses did has been attributed generally to PAHs which are pres- not induce similar lesions, indicating marked strain ent in unrefined or poorly refined oils. The materials variability. Lipogranulomas associated with the inges- tion of mineral oil have been reported in humans. The of interest to the current inquiry are highly refined and comparative morphology of the lesions seen in the Fi- contain no known carcinogenic PAHs or barely detect- scher rat study and those observed in the human are able levels of them. discussed and differences are highlighted. The lesions Recent 90-day feeding studies of various levels of in the human are not believed to progress to lesions highly refined mineral oils and waxes in the Fischer of clinical significance. The pathogenesis of the lesions 344 rat have resulted in the occurrence of granulomas induced in Fischer rats and in humans is discussed in the liver and histiocytosis in mesenteric lymph nodes and it is concluded that the majority, if not all of the by certain of these mineral hydrocarbons (Baldwin et lesions, in the rats are of no significance for humans. al., 1992). These findings contrast with negative find- The possibility that a small proportion of cases of gran- ings reported in studies using other rat strains and ulomatous hepatitis in humans may represent an atyp- other species (Shubik et al., 1962; McKee et al., 1987). ical response to mineral hydrocarbons may need fur- The refined mineral hydrocarbon products used in ther investigation.  1998 Academic Press the Fischer 344 rat studies are representative of mate- rials used in a number of applications that have a po- tential for causing low-level human exposure. These INTRODUCTION uses include direct food additives, food packaging, cos- metics, veterinary vaccines, and pharmaceutical agents. A 1990 market survey of food grade mineral The term ‘‘mineral hydrocarbon’’ is used as a generic hydrocarbons revealed that 42% of the total market description for materials derived from petroleum includ- resulted from polystyrene (used both in food and non- ing mineral oils and waxes of various kinds. Medicinal and food grade mineral hydrocarbons are prepared from food applications), 21% from cosmetics, 10% from phar- 75 0273-2300/98 $25.00 Copyright  1998 by Academic Press All rights of reproduction in any form reserved.