Carl R. Mackerer

In vitro and in vivo percutaneous absorption of benzo[a]pyrene from petroleum crude-fortified soil in the rat.

Concern regarding dermal exposure to soils contaminated with potentially toxic materials such as dioxins, pesticides, heavy metals, polynuclear aromatics (PNA) and petroleum products containing PNA, has prompted government and private sectors to examine and formulate dermal risk assessment methodologies for contaminated soils. In the absence of experimentally determined percutaneous absorption values, many risk assessment schemes substitute available animal toxicology data on the pure contaminant, estimate dermal penetration of pure contaminant based on physicochemical models or, in the extreme, assume 100% bioavailability of the contaminant from soil. Risk assessment based on these approaches is likely to result in an overestimate of dermal bioavailability of contaminants from soil, particularly for the water insoluble lipophilic compounds found in petroleum products. The authors have performed dermal bioavailability studies on a variety of lipophilic materials and special emphasis has been placed on the development and implementation of a modified in vitro technique for evaluating the percutaneous absorption of PNA and PNA mixtures. In the present paper, they apply the modified in vitro technique to evaluate the percutaneous absorption of ({sup 3}H-labelled) benzo(a)pyrene (BaP) in petroleum crude oil sorbed on soil and compare the results with those for the percutaneous absorption of BaP from crude oilmorexa0» alone. Results of the in vitro experiments are compared with findings from parallel in vivo experiments.«xa0less

Predicting carcinogenicity of petroleum distillation fractions using a modified Salmonella mutagenicity assay

The Ames Salmonella/microsomal activation mutagenesis assay has been modified to improve sensitivity and reproducibility to complex mixtures derived from the refining and processing of petroleum. Oil samples were dissolved in cyclohexane and subsequently extracted with dimethyl sulfoxide to produce aqueous compatible solutions which readily interact with tester bacteria. Also, the liver homogenate (S-9) and NADP cofactor concentrations were increased and hamster rather than rat liver S-9 was used. The initial slope of the dose response curve relating mutagenicity (revertants per plate) to the dose of extract added was used as an index of mutagenic activity, this slope was obtained through a computerized curve fitting procedure. The modified assay was used to rank 18 oil samples for mutagenic activity, this ranking correlates highly (r = 0.92) with potency rankings of the same samples previously determined from dermal carcinogenicity bioassays. Sensitivity and reproducibility of the assay are sufficient to permit routine use for detecting potential carcinogenic activity of individual refinery streams and blends which contain components boiling above 500°F.

Estimation of the dermal carcinogenic activity of petroleum fractions using a modified Ames assay

The Ames Salmonella/microsomal activation mutagenesis assay has been adapted to improve sensitivity to complex hydrocarbon mixtures produced by the refining of petroleum. Extraction of oil samples with dimethyl sulfoxide produces aqueous-compatible solutions that more easily interact with the tester bacteria. These extracts, therefore, produce higher revertant values than do equivalent volumes of oil delivered neat or dissolved in organic solvent. Parallel increases in the liver microsomal S-9 concentration further improve the sensitivity of the assay, allowing detection of mutagenicity in otherwise inactive samples. The effect of increased microsomal fraction from rodent liver is apparently attributable to the higher levels of activating enzymes rather than to the concomitant increase in the overall hydrophobicity of the test system. The modified assay has been used to rank thirteen petroleum-derived oils and a corn oil control for relative mutagenic activity. This ranking closely correlates (r = 0.97) with potency rankings of the same samples previously determined from dermal carcinogenicity bioassays.

Health Effects of the Alkylbenzenes. II. Ylenes

The alkylbenzenes are a class of six-membered ring aromatic compounds that have a variety of alkyl groups attached. These chemicals are liquids with relatively low boiling points used primarily as solvents or as starting materials in the synthesis of other chemicals and drugs. They are integral components of gasoline, distillate fuels and other petroleum products and are economically important in the chemical, petroleum, pharmaceutical, polymer, paint and dye industries. Alkylbenzenes such as toluene, the xylenes, ethylbenzene, styrene and cumene are produced and utilized in large quantities and therefore, present the possibility of exposure to humans and to wildlife. Fortunately, the toxicity of alkylbenzenes has been found to be rather low and therefore, the human and environmental risks are probably low. In modern industrial activities, exposures to the alkylbenzenes are minimized by workplace controls or personal protective equipment which meet guidelines for maximum allowable exposure concentrations that have been established for the workplace. Nevertheless, considerable quantities of alkylbenzenes are released to the environment each year through solvent and fuel evaporation, accidental spills and misuse, and considerable toxicological infonnationfor these materials has appeared in the recent literature. This present paper, the second in a series reviewing the potential health effects of alkylbenzenes, covers the toxicology and disposition of the dimethyl-substituted benzenes (the .xylenes) in animals and man.

Correlation of Systemic and Developmental Toxicities with Chemical Component Classes of Refinery Streams

Refinery streams are complex mixtures, but of a relatively few homologous series of hydrocarbons (paraffins, olefins, naphthenics, and aromatics). Studies were performed to determine if systemic and developmental toxicity were related to the presence and levels of certain classes of refinery stream components. We have performed systemic toxicology studies in the rat on 13 refinery streams: Clarified Slurry Oil, Coker Light Gas Oil, Distillate Aromatic Extract, Heavy Atmospheric Gas Oil, Heavy Coker Gas Oil (from three refineries), Heavy Vacuum Gas Oil, Light Catalytically Cracked Naphtha, Light Cycle Oil, Syntower Bottoms, Vacuum Tower Overhead, and Visbreaker Gas Oil. Rats were exposed via repeated dermal administration (daily) at several dose levels. Developmental toxicology studies were performed on these same streams with the following exceptions: only two Heavy Coker Gas Oils were tested and Visbreaker Gas Oil was not tested. End points for systemic toxicity (13-week) studies included skin irritation, body and organ weights, hematology, and serum chemistry; for developmental toxicity studies some of these same end points (excluding hematology) were considered, but they also included resorption and fetal body weight. In general, toxicity was correlated with concentrations of polycyclic aromatic compounds (PAC) composed of 3, 4, 5, 6, and/or 7 rings (decreased thymus weight, increased liver weight, aberrant hematology and serum chemistry, increased incidence of resorption, decreased fetal body weight), PAC containing nonbasic nitrogen heteroatoms (increased mortality, decreased body weight, decreased thymus weight, increased liver weight, decreased hemoglobin content and hematocrit level, decreased fetal body weight), and/or PAC containing sulfur heteroatoms (decreased red blood cell and platelet counts, increased sorbitol dehydrogenase.)(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous Absorption of Anthracene in the Rat: Comparison of in Vivo and in Vitro Results:

The present study was conducted to evaluate the applicability of in vitro percutaneous absorption techniques to estimate in vivo absorption of polynuclear aromatic (PNA) compounds commonly found in mineral oils. The percutaneous absorption of 14C-labeled anthracene, a three-ring PNA, was compared in a six-day in vivo and in vitro experiment with female Sprague-Dawley rats following a single topical dose (9.3 μg/cm2). In vivo absorption was mea sured by the presence of 14C radioactivity in urine, feces and tissues and in vitro absorption by penetration of radioactivity through excised skin into the receptor fluid of Franz-type diffusion cells. Several modifications of standard diffusion cell techniques were used which are known to enhance the absorption of lipophilic compounds. Anthracene was observed to readily penetrate the skin in both experiments and the total amounts absorbed in vivo and in vivo were seen to gradually coalesce over time. Within six days after application, 52.3 and 55.9% of the administered anthracene was absorbed in vivo and in vitro, respectively.

Health effects of oil mists: a brief review.

Metal cutting/grinding fluids are of three basic types: straight oil (insoluble), oil-in-water emulsions (soluble) and synthetic/semi-synthetic. All contain a variety of additives to improve performance. Human exposure occurs primarily by direct skin contact with the liquid or by skin and respiratory contact after fluid misting. Dermatitis caused by primary or direct skin irritation is the most prevalent health effect of exposure to cutting fluids. Occasionally allergic dermatitis is seen which is related to the development of sensitization to one or more of the additive components. Recent studies indicate that long-term exposure to cutting fluids does not result in increased incidences of lung cancer, urinary bladder cancer, gastrointestinal cancer, or death from non-malignant respiratory diseases. Long-term exposure to certain cutting fluids, however, is believed to have resulted in certain types of skin cancer, especially scrotal cancer. It is likely that these carcinogenic responses were caused by contact with polycyclic aromatic compounds (PCA) of 3–7 rings. Modern base oils which are severely refined have very low levels of PCA, are not carcinogenic in animal bioassays, and are unlikely to be carcinogenic in man. This is not necessarily true for re-refined oils which may contain significant levels of PCA and polychlorinated biphenyls derived from coming-ling used cutting oils with used engine oils and transformer oils. Cutting oils, themselves, generally do not accumulate significant levels of carcinogenic PCA during use. Additives, in theory, can cause a variety of health effects either directly or through the generation of reaction products such as nitrosamines. In actual use, adverse health effects appear to be limited to occasional instances of allergic contact dermatitis. Nitrosamines are extremely carcinogenic in test animals; although no human cancer cases directly attributable to nitrosamine contamination have been observed, nitrosating agents and amines should not be combined in cutting fluid formulations. It is difficult to anticipate or predict the potential toxicity of a particular cutting fluid formulation because of the presence of variable amounts of proprietary additives which, themselves, are often complex reaction mixtures. Thus, each additive and final formulation must be evaluated on a case by case basis to appropriately assess potential health hazards.

Health Effects of the Alkylbenzenes. I. Toluene

The alkylbenzenes, toluene being the most common example, represent a class of six-membered ring aromatic compounds that have a variety of alkyl groups attached. These chemicals are liquids with relatively low boiling points and are used primarily as solvents or as starting materials in the synthesis of other chemicals and drugs. They are also integral components of gasoline, distillate fuels and other petroleum products. These substituted aromatics are economically important in the chemical, petroleum, pharmaceutical, polymer, paint and dye industries. Alkylbenzenes such as toluene, xylene, ethylbenzene, styrene and cumene are toxicologically important since they are produced, used or disposed of in the largest quantities and therefore might pose significant and potential health risks to man and the environment. In general, the toxicity of alkylbenzenes has been found to be relatively low. Also, for the most part, human and environmental risks are low; however, there may be a few operations where the potential for high exposure could exist. These exposures are minimized by workplace controls or personal protective equipment. Furthermore, health risks for humans are minimized by guidelines for maximum allowable exposure concentrations which have been established for the workplace. This present paper reviews the toxicology and disposition of toluene in animals and humans.

Comparison of Biological and Chemical Predictors of Dermal Carcinogenicity of Petroleum Oils

Abstract. Various methods have been proposed as a basis for cancer hazard labelling of petroleum products. The Institute of Petroleum analytical method termed IP 346/80 was recently recommended to the European Union as the preferred method for this purpose. In this report we compare IP 346/80 with several other predictors of dermal carcinogenicity, including the Mobil PAC Method, the Modified Ames Test (ASTM Method E 1687-95), and the 32P-postlabelling assay for DNA adducts. Oils for assay were selected from a repository of samples previously subjected to mouse skin-painting bioassay. 120 oils were tested in the Modified Ames Assay, 57 by the Mobil PAC Method, 50 by Method IP 346/80, and 48 by the postlabelling procedure. The ability of each assay to distinguish between carcinogenic and noncarcinogenic oils was examined at various suggested discriminators, e.g. Mutagenicity Indices (MI) of 1.0 and 2.0, 3-7 ring PAC contents of 1% and 2% (w/w), and IP 346/80 DMSO-extractables of 2% and 3% (w/w). Various ad...

Identification of formaldehyde as the metabolite responsible for the mutagenicity of methyl tertiary-butyl ether in the activated mouse lymphoma assay.

Abstract Methyl tertiary-butyl ether (MTBE), which is added to gasoline as an octane enhancer and to reduce automotive emissions, has been evaluated in numerous toxicological tests, including those for genotoxicity. MTBE did not show any mutagenic potential in the Ames bacterial assay or any clastogenicity in cytogenetic tests. However, it has been shown to be mutagenic in an in vitro gene mutation assay using mouse lymphoma cells when tested in the presence, but not in the absence, of a rat liver-derived metabolic activation system (S-9). In the present study, MTBE was tested to determine if formaldehyde, in the presence of the S-9, was responsible for the observed mutagenicity. A modification of the mouse lymphoma assay was employed which permits determination of whether a suspect material is mutagenic because it contains or is metabolized to formaldehyde. In the modified assay, the enzyme formaldehyde dehydrogenase (FDH) and its co-factor, NAD+ are added in large excess during the exposure period so that any formaldehyde produced in the system is/sp rapidly converted to formic acid which is not genotoxic. An MTBE dose-responsive increase in the frequency of mutants and in cytotoxicity occurred without FDH present, and this effect was greatly reduced in the presence of FDH+NAD+. The findings clearly demonstrate that formaldehyde derived from MTBE is responsible for mutagenicity of MTBE in the activated mouse lymphoma assay. Furthermore, the results suggest that the lack of mutagenicity/clastogenicity seen with MTBE in other in vitro assays might have resulted from inadequacies in the test systems employed for those assays.